Genetic polymorphisms associated with venous thrombosis, methods of detection and uses thereof

ABSTRACT

The present invention is based on the discovery of genetic polymorphisms that are associated with venous thrombosis. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

FIELD OF THE INVENTION

The present invention is in the field of thrombosis diagnosis andtherapy. In particular, the present invention relates to specific singlenucleotide polymorphisms (SNPs) in the human genome, and theirassociation with venous thrombosis (VT) and related pathologies. Basedon differences in allele frequencies in the patient population relativeto normal individuals, the naturally-occurring SNPs disclosed herein canbe used as targets for the design of diagnostic reagents and thedevelopment of therapeutic agents, as well as for disease associationand linkage analyses. In particular, the SNPs of the present inventionare useful for identifying an individual who is at an increased ordecreased risk of developing venous thrombosis and for early detectionof the disease, for providing clinically important information for theprevention and/or treatment of venous thrombosis, for screening andselecting therapeutic agents, and for predicting a patient's response totherapeutic agents. The SNPs disclosed herein are also useful for humanidentification applications. Methods, assays, kits, and reagents fordetecting the presence of these polymorphisms and their encoded productsare provided.

BACKGROUND OF THE INVENTION Venous Thrombosis (VT)

The development of a blood clot is known as thrombosis. Venousthrombosis (VT) is the formation of a blood clot in the veins. VT mayalso be referred to as venous thromboembolism (VTE). Over 200,000 newcases of VT occur annually. Of these, 30 percent of patients die withinthree days; one in five suffer sudden death due to pulmonary embolism(PE) (Seminars in Thrombosis and Hemostasis, 2002, Vol. 28, Suppl. 2)(Stein et al., Chest 2002; 122(3):960-962, further describes PE).Caucasians and African-Americans have a significantly higher incidencethan Hispanics, Asians or Pacific Islanders (White, Circulation 107(23Suppl 1):I4-8 Review, 2003).

Several conditions can lead to an increased tendency to develop bloodclots in the veins or arteries (National Hemophilia Foundation, HemAwarenewsletter, Vol. 6 (5), 2001), and such conditions may be inherited(genetic) or acquired. Examples of acquired conditions are surgery andtrauma, prolonged immobilization, cancer, myeloproliferative disorders,age, hormone therapy, and even pregnancy, all of which may result inthrombosis (Seligsohn et al., New Eng J Med 344(16):1222-1231, 2001 andHeit et al., Thromb Haemost 2001; 86(1):452-463). Family and twinstudies indicate that inherited (genetic) causes account for about 60%of the risk for DVT (Souto et al., Am J Hum Genet. 2000; 67(6):1452-1459; Larsen et al., Epidemiology 2003; 14(3):328-332). Inheritedcauses include polymorphisms in any of several different clotting,anticoagulant, or thrombolytic factors, such as the factor V gene (thefactor V Leiden (FVL) variant), prothrombin gene (factor II), andmethylenetetrahydrofolate reductase gene (MTHFR). Other likely inheritedcauses are an increase in the expression levels of the factors VIII, IXor XI, or fibrinogen genes (Seligsohn et al., New Eng J Med 344(16):1222-1231, 2001). Deficiencies of natural anticoagulants antithrombin,protein C and protein S are strong risk factors for DVT; however, thevariants causing these deficiencies are rare, and explain only about 1%of all DVTs (Rosendaal et al., Lancet 1999; 353(9159): 1167-1173). Thefactor V Leiden (FVL) and prothrombin G20210A genetic variants have beenconsistently found to be associated with DVT (Bertina et al., Nature1994; 369(6475):64-67 and Poort et al., Blood 1996; 88(10):3698-3703)but still only explain a fraction of the DVT events (Rosendaal, Lancet1999; 353(9159):1167-1173; Bertina et al., Nature 1994; 369(6475):64-67;Poort et al., Blood 1996; 88(10):3698-3703). Elevated plasmaconcentrations of coagulation factors (e.g., VIII, IX, X, and XI) havealso been shown to be important risk factors for DVT (Kyrle et al., NEngl J Med. 2000; 343:457-462; van Hylckama Vlieg et al., Blood. 2000;95:3678-3682; de Visser et al., Thromb Haemost. 2001; 85:1011-1017; andMeijers et al., N Engl J Med. 2000; 342:696-701, respectively).

About one-third of patients with symptomatic VT manifest pulmonaryembolism (PE), whereas two-thirds manifest deep vein thrombosis (DVT)(White, Circulation 107(23 Suppl 1):I4-8 Review, 2003). DVT is an acuteVT in a deep vein, usually in the thigh, legs, or pelvis, and it is aserious and potentially fatal disorder that can arise as a complicationfor hospital patients, but may also affect otherwise healthy people(Lensing et al., Lancet 353:479-485, 1999). Large blood clots in VT mayinterfere with blood circulation and impede normal blood flow. In someinstances, blood clots may break off and travel to distant major organssuch as the brain, heart or lungs as in PE and result in fatality. Thereis evidence to suggest that patients with a first episode of VT betreated with anticoagulant agents (Kearon et al., New Engl J Med340:901-907, 1999).

VT is a chronic disease with episodic recurrence; about 30% of patientsdevelop recurrence within 10 years after a first occurrence of VT (Heitet al., Arch Intern Med. 2000; 160: 761-768; Heit et al., Thromb Haemost2001; 86(1):452-463; and Schulman et al., J Thromb Haemost. 2006; 4:732-742). Recurrence of VT may be referred to herein as recurrent VT.The hazard of recurrence varies with the time since the incident eventand is highest within the first 6 to 12 months. Although anticoagulationis effective in preventing recurrence, the duration of anticoagulationdoes not affect the risk of recurrence once primary therapy for theincident event is stopped (Schulman et al., J Thromb Haemost. 2006; 4:732-742 and van Dongen et al., Arch Intern Med. 2003; 163: 1285-1293).Independent predictors of recurrence include male gender (McRae et al.,Lancet. 2006; 368: 371-378), increasing patient age and body mass index,neurological disease with leg paresis, and active cancer (Cushman etal., Am J Med. 2004; 117: 19-25; Heit et al., Arch Intern Med. 2000;160: 761-768; Schulman et al., J Thromb Haemost. 2006; 4: 732-742; andBaglin et al., Lancet. 2003; 362: 523-526). Additional predictorsinclude “idiopathic” venous thrombosis (Baglin et al., Lancet. 2003;362: 523-526), a lupus anticoagulant or antiphospholipid antibody(Kearon et al., N Engl J Med. 1999; 340: 901-907 and Schulman et al., AmJ Med. 1998; 104: 332-338), antithrombin, protein C or protein Sdeficiency (van den Belt et al., Arch Intern Med. 1997; 157: 227-232),and possibly persistently increased plasma fibrin D-dimer (Palareti etal., N Engl J Med. 2006; 355: 1780-1789) and residual venous thrombosis(Prandoni et al., Ann Intern Med. 2002; 137: 955-960).

VT and cancer can be coincident. According to clinical dataprospectively collected on the population of Olmsted County, Minnesota,since 1966, the annual incidence of a first episode of DVT or PE in thegeneral population is 117 of 100,000. Cancer alone was associated with a4.1-fold risk of thrombosis, whereas chemotherapy increased the risk6.5-fold. Combining these estimates yields an approximate annualincidence of VT in cancer patients of 1 in 200 cancer patients (Lee etal., Circulation. 2003; 107:I-17-I-21). Extrinsic factors such assurgery, hormonal therapy, chemotherapy, and long-term use of centralvenous catheters increase the cancer-associated prethrombotic state.Post-operative thrombosis occurs more frequently in patients with canceras compared to non-neoplastic patients (Rarh et al., Blood coagulationand fibrinolysis 1992; 3:451).

Thus, there is an urgent need for novel genetic markers that arepredictive of predisposition to VT, particularly for individuals who areunrecognized as having a predisposition to developing the disease basedon conventional risk factors. Such genetic markers may enable screeningof VT in much larger populations compared with the populations that cancurrently be evaluated by using existing risk factors and biomarkers.The availability of a genetic test may allow, for example, appropriatepreventive treatments for acute venous thrombotic events to be providedfor high risk individuals (such preventive treatments may include, forexample, anticoagulant agents). Moreover, the discovery of geneticmarkers associated with VT may provide novel targets for therapeuticintervention or preventive treatments.

SNPs

The genomes of all organisms undergo spontaneous mutation in the courseof their continuing evolution, generating variant forms of progenitorgenetic sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). Avariant form may confer an evolutionary advantage or disadvantagerelative to a progenitor form or may be neutral. In some instances, avariant form confers an evolutionary advantage to the species and iseventually incorporated into the DNA of many or most members of thespecies and effectively becomes the progenitor form. Additionally, theeffects of a variant form may be both beneficial and detrimental,depending on the circumstances. For example, a heterozygous sickle cellmutation confers resistance to malaria, but a homozygous sickle cellmutation is usually lethal. In many cases, both progenitor and variantforms survive and co-exist in a species population. The coexistence ofmultiple forms of a genetic sequence gives rise to geneticpolymorphisms, including SNPs.

Approximately 90% of all genetic polymorphisms in the human genome areSNPs. SNPs are single base positions in DNA at which different alleles,or alternative nucleotides, exist in a population. The SNP position(interchangeably referred to herein as SNP, SNP site, SNP locus, SNPmarker, or marker) is usually preceded by and followed by highlyconserved sequences of the allele (e.g., sequences that vary in lessthan 1/100 or 1/1000 members of the populations). An individual may behomozygous or heterozygous for an allele at each SNP position. A SNPcan, in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at thepolymorphic site. Substitutions can be transitions or transversions. Atransition is the replacement of one purine nucleotide by another purinenucleotide, or one pyrimidine by another pyrimidine. A transversion isthe replacement of a purine by a pyrimidine, or vice versa. A SNP mayalso be a single base insertion or deletion variant referred to as an“indel” (Weber et al., “Human diallelic insertion/deletionpolymorphisms,” Am J Hum Genet 2002 October; 71(4):854-62).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP,”“polymorphism,” “mutation,” “mutant,” “variation,” and “variant” areused herein interchangeably), is one that does not result in a change ofamino acid due to the degeneracy of the genetic code. A substitutionthat changes a codon coding for one amino acid to a codon coding for adifferent amino acid (i.e., a non-synonymous codon change) is referredto as a missense mutation. A nonsense mutation results in a type ofnon-synonymous codon change in which a stop codon is formed, therebyleading to premature termination of a polypeptide chain and a truncatedprotein. A read-through mutation is another type of non-synonymous codonchange that causes the destruction of a stop codon, thereby resulting inan extended polypeptide product. While SNPs can be bi-, tri-, ortetra-allelic, the vast majority of the SNPs are bi-allelic, and arethus often referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individualSNPs and/or haplotypes, which are groups of SNPs that are generallyinherited together. Haplotypes can have stronger correlations withdiseases or other phenotypic effects compared with individual SNPs, andtherefore may provide increased diagnostic accuracy in some cases(Stephens et al. Science 293, 489-493, 20 Jul. 2001).

Causative SNPs are those SNPs that produce alterations in geneexpression or in the expression, structure, and/or function of a geneproduct, and therefore are most predictive of a possible clinicalphenotype. One such class includes SNPs falling within regions of genesencoding a polypeptide product, i.e. cSNPs. These SNPs may result in analteration of the amino acid sequence of the polypeptide product (i.e.,non-synonymous codon changes) and give rise to the expression of adefective or other variant protein. Furthermore, in the case of nonsensemutations, a SNP may lead to premature termination of a polypeptideproduct. Such variant products can result in a pathological condition,e.g., genetic disease. Examples of genes in which a SNP within a codingsequence causes a genetic disease include sickle cell anemia and cysticfibrosis.

Causative SNPs do not necessarily have to occur in coding regions;causative SNPs can occur in, for example, any genetic region that canultimately affect the expression, structure, and/or activity of theprotein encoded by a nucleic acid. Such genetic regions include, forexample, those involved in transcription, such as SNPs in transcriptionfactor binding domains, SNPs in promoter regions, in areas involved intranscript processing, such as SNPs at intron-exon boundaries that maycause defective splicing, or SNPs in mRNA processing signal sequencessuch as polyadenylation signal regions. Some SNPs that are not causativeSNPs nevertheless are in close association with, and therefore segregatewith, a disease-causing sequence. In this situation, the presence of aSNP correlates with the presence of, or predisposition to, or anincreased risk in developing the disease. These SNPs, although notcausative, are nonetheless also useful for diagnostics, diseasepredisposition screening, and other uses.

An association study of a SNP and a specific disorder involvesdetermining the presence or frequency of the SNP allele in biologicalsamples from individuals with the disorder of interest, such as VT, andcomparing the information to that of controls (i.e., individuals who donot have the disorder; controls may be also referred to as “healthy” or“normal” individuals) who are preferably of similar age and race. Theappropriate selection of patients and controls is important to thesuccess of SNP association studies. Therefore, a pool of individualswith well-characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biologicalsample obtained from a diseased individual, and compared to controlsamples, and selected for its increased (or decreased) occurrence in aspecific pathological condition, such as pathologies related to VT. Oncea statistically significant association is established between one ormore SNP(s) and a pathological condition (or other phenotype) ofinterest, then the region around the SNP can optionally be thoroughlyscreened to identify the causative genetic locus/sequence(s) (e.g.,causative SNP/mutation, gene, regulatory region, etc.) that influencesthe pathological condition or phenotype. Association studies may beconducted within the general population and are not limited to studiesperformed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment withpharmaceuticals is often heterogeneous. There is a continuing need toimprove pharmaceutical agent design and therapy. In that regard, SNPscan be used to identify patients most suited to therapy with particularpharmaceutical agents (this is often termed “pharmacogenomics”).Similarly, SNPs can be used to exclude patients from certain treatmentdue to the patient's increased likelihood of developing toxic sideeffects or their likelihood of not responding to the treatment.Pharmacogenomics can also be used in pharmaceutical research to assistthe drug development and selection process. (Linder et al. (1997),Clinical Chemistry, 43, 254; Marshall (1997), Nature Biotechnology, 15,1249; International Patent Application WO 97/40462, Spectra Biomedical;and Schafer et al. (1998), Nature Biotechnology, 16: 3).

SUMMARY OF THE INVENTION

The present invention relates to the identification of novel SNPs,unique combinations of such SNPs, and haplotypes of SNPs that areassociated with VT. The polymorphisms disclosed herein are directlyuseful as targets for the design of diagnostic reagents and thedevelopment of therapeutic agents for use in the diagnosis and treatmentof VT.

Based on the identification of SNPs associated with VT, the presentinvention also provides methods of detecting these variants as well asthe design and preparation of detection reagents needed to accomplishthis task. The invention specifically provides, for example, novel SNPsin genetic sequences involved in VT, isolated nucleic acid molecules(including, for example, DNA and RNA molecules) containing these SNPs,variant proteins encoded by nucleic acid molecules containing such SNPs,antibodies to the encoded variant proteins, computer-based and datastorage systems containing the novel SNP information, methods ofdetecting these SNPs in a test sample, methods of identifyingindividuals who have an altered (i.e., increased or decreased) risk ofdeveloping VT based on the presence or absence of one or more particularnucleotides (alleles) at one or more SNP sites disclosed herein or thedetection of one or more encoded variant products (e.g., variant mRNAtranscripts or variant proteins), methods of identifying individuals whoare more or less likely to respond to a treatment (or more or lesslikely to experience undesirable side effects from a treatment, etc.),methods of screening for compounds useful in the treatment of a disorderassociated with a variant gene/protein, compounds identified by thesemethods, methods of treating disorders mediated by a variantgene/protein, methods of using the novel SNPs of the present inventionfor human identification, etc.

In Tables 1-2, the present invention provides gene information,references to the identification of transcript sequences (SEQ ID NOS:1-125), encoded amino acid sequences (SEQ ID NOS: 126-250), genomicsequences (SEQ ID NOS: 404-601), transcript-based context sequences (SEQID NOS: 251-403) and genomic-based context sequences (SEQ ID NOS:602-1587) that contain the SNPs of the present invention, and extensiveSNP information that includes observed alleles, allele frequencies,populations/ethnic groups in which alleles have been observed,information about the type of SNP and corresponding functional effect,and, for cSNPs, information about the encoded polypeptide product. Theactual transcript sequences (SEQ ID NOS: 1-125), amino acid sequences(SEQ ID NOS: 126-250), genomic sequences (SEQ ID NOS: 404-601),transcript-based SNP context sequences (SEQ ID NOS: 251-403), andgenomic-based SNP context sequences (SEQ ID NOS: 602-1587, as well asSEQ ID NOS: 2557-2580), together with primer sequences (SEQ ID NOS:1588-2556) are provided in the Sequence Listing.

In one embodiment of the invention, applicants teach a method foridentifying an individual who has an altered risk for developing VT,comprising detecting a single nucleotide polymorphism (SNP) in, or a SNPthat is in linkage disequilibrium (LD) with, any one of the nucleotidesequences of SEQ ID NOS: 1-125, SEQ ID NOS: 126-250, SEQ ID NOS:251-403, and SEQ ID NOS: 404-601 in said individual's nucleic acids,wherein the SNP is as specified in Table 1 and Table 2, respectively,and the presence of the SNP is correlated with an altered risk for VT insaid individual. In a specific embodiment of the present invention, SNPsthat occur naturally in the human genome are provided as isolatednucleic acid molecules. These SNPs are associated with VT, such thatthey can have a variety of uses in the diagnosis and/or treatment of VTand related pathologies. In an alternative embodiment, a nucleic acid ofthe invention is an amplified polynucleotide, which is produced byamplification of a SNP-containing nucleic acid template. In anotherembodiment, the invention provides for a variant protein that is encodedby a nucleic acid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting aSNP in the context of its naturally-occurring flanking nucleotidesequences (which can be, e.g., either DNA or mRNA) is provided. Inparticular, such a reagent may be in the form of, for example, ahybridization probe or an amplification primer that is useful in thespecific detection of a SNP of interest. In an alternative embodiment, aprotein detection reagent is used to detect a variant protein that isencoded by a nucleic acid molecule containing a SNP disclosed herein. Apreferred embodiment of a protein detection reagent is an antibody or anantigen-reactive antibody fragment.

Various embodiments of the invention also provide kits comprising SNPdetection reagents, and methods for detecting the SNPs disclosed hereinby employing detection reagents. In a specific embodiment, the presentinvention provides for a method of identifying an individual having anincreased or decreased risk of developing VT by detecting the presenceor absence of one or more SNP alleles disclosed herein. In anotherembodiment, a method for diagnosis of VT by detecting the presence orabsence of one or more SNP alleles disclosed herein is provided.

The nucleic acid molecules of the invention can be inserted in anexpression vector, such as to produce a variant protein in a host cell.Thus, the present invention also provides for a vector comprising aSNP-containing nucleic acid molecule, genetically-engineered host cellscontaining the vector, and methods for expressing a recombinant variantprotein using such host cells. In another specific embodiment, the hostcells, SNP-containing nucleic acid molecules, and/or variant proteinscan be used as targets in a method for screening and identifyingtherapeutic agents or pharmaceutical compounds useful in the treatmentof VT.

An aspect of this invention is a method for treating VT in a humansubject wherein said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1-2, which method comprisesadministering to said human subject a therapeutically orprophylactically effective amount of one or more agents counteractingthe effects of the disease, such as by inhibiting (or stimulating) theactivity of the gene, transcript, and/or encoded protein identified inTables 1-2.

Certain embodiments of the invention provide methods for reducing riskof VT (either a first VT or recurrent VT) in a human who has beenidentified as having an increased risk for VT due to the presence orabsence of a SNP disclosed herein, in which the methods compriseadministering to the human an effective amount of a therapeutic agent toreduce the risk for VT. In certain embodiments, the methods includetesting nucleic acid from said human for the presence or absence of theSNP. In certain embodiments, the therapeutic agent is at least one of ananticoagulant agent and an antiplatelet agent.

Certain embodiments of the invention provide methods for determiningwhether a human should be administered a therapeutic agent for reducingtheir risk for VT (which can be either a first VT or a recurrent VT)based on the presence or absence of a SNP disclosed herein. In certainembodiments, the therapeutic agent is at least one of an anticoagulantagent and an antiplatelet agent.

Examples of anticoagulant agents include, but are not limited to,coumarines (vitamin K antagonists) such as warfarin (coumadin),acenocoumarol, phenprocoumon, and phenindione; heparin and derivativesubstances such as low molecular weight heparin; factor Xa inhibitorssuch as Fondaparinux, Idraparinux, and other synthetic pentasaccharideinhibitors of factor Xa; and thrombin inhibitors such as argatroban,lepirudin, bivalirudin, and dabigatran. Examples of antiplatelet agentsinclude, but are not limited to, cyclooxygenase inhibitors such asaspirin, and adenosine diphosphate (ADP) receptor inhibitors such asclopidogrel (Plavix) and prasugrel (Effient).

Certain embodiments of the invention provide methods for conducting aclinical trial of a therapeutic agent in which a human is selected forinclusion in the clinical trial and/or assigned to a particular group(e.g., an “arm” or “cohort” of the trial) within a clinical trial basedon the presence or absence of a SNP disclosed herein. In certainembodiments, the therapeutic agent is at least one of an anticoagulantagent and an antiplatelet agent.

Another aspect of this invention is a method for identifying an agentuseful in therapeutically or prophylactically treating VT in a humansubject wherein said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1-2, which method comprisescontacting the gene, transcript, or encoded protein with a candidateagent under conditions suitable to allow formation of a binding complexbetween the gene, transcript, or encoded protein and the candidate agentand detecting the formation of the binding complex, wherein the presenceof the complex identifies said agent.

Another aspect of this invention is a method for treating VT in a humansubject, which method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1-2, and

(ii) administering to said subject a therapeutically or prophylacticallyeffective amount of one or more agents counteracting the effects of thedisease such as anticoagulant or antiplatelet agents.

Many other uses and advantages of the present invention will be apparentto those skilled in the art upon review of the detailed description ofthe preferred embodiments herein. Solely for clarity of discussion, theinvention is described in the sections below by way of non-limitingexamples.

DESCRIPTION OF THE TEXT (ASCII) FILES SUBMITTED ELECTRONICALLY VIAEFS-WEB

The following three text (ASCII) files are submitted electronically viaEFS-Web as part of the instant application:

1) File SEQLIST_CD000023.txt provides the Sequence Listing. The SequenceListing provides the transcript sequences (SEQ ID NOS: 1-125) andprotein sequences (SEQ ID NOS: 126-250) as referred to in Table 1, andgenomic sequences (SEQ ID NOS: 404-601) as referred to in Table 2, foreach VT-associated gene or genomic region (for intergenic SNPs) thatcontains one or more SNPs of the present invention. Also provided in theSequence Listing are context sequences flanking each SNP, including bothtranscript-based context sequences as referred to in Table 1 (SEQ IDNOS: 251-403) and genomic-based context sequences as referred to inTable 2 (SEQ ID NOS: 602-1587). In addition, the Sequence Listingprovides the primer sequences from Table 3 (SEQ ID NOS: 1588-2556),which are oligonucleotides that have been synthesized and used in thelaboratory to assay the SNPs disclosed in Tables 5-13 during the courseof association studies to verify the association of these SNPs with VT.The context sequences generally provide 100 bp upstream (5′) and 100 bpdownstream (3′) of each SNP, with the SNP in the middle of the contextsequence, for a total of 200 bp of context sequence surrounding eachSNP. The Sequence Listing also provides SEQ ID NOS: 2557-2580, which areexemplary genomic context sequences for certain SNPs presented in Table8 and Table 17.

File SEQLIST_CD000023.txt is 24,327 KB in size, and was created on Mar.12, 2009.

2) File TABLE1_CD000023.txt provides Table 1. File Table1_CD000023.txtis 175 KB in size, and was created on Mar. 11, 2009.

3) File TABLE2_CD000023.txt provides Table 2. File Table2_CD000023.txtis 739 KB in size, and was created on Mar. 11, 2009.

These three files are hereby incorporated by reference pursuant to 37CFR 1.77(b)(4).

Description of Table 1 and Table 2

Table 1 and Table 2 (both of which are ASCII text files submittedelectronically via EFS-Web) disclose the SNP and associatedgene/transcript/protein information of the present invention. For eachgene, Table 1 provides a header containing gene, transcript and proteininformation, followed by a transcript and protein sequence identifier(SEQ ID), and then SNP information regarding each SNP found in thatgene/transcript including the transcript context sequence. For each genein Table 2, a header is provided that contains gene and genomicinformation, followed by a genomic sequence identifier (SEQ ID) and thenSNP information regarding each SNP found in that gene, including thegenomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table1 presents the SNPs relative to their transcript sequences and encodedprotein sequences, whereas Table 2 presents the SNPs relative to theirgenomic sequences. In some instances Table 2 may also include, after thelast gene sequence, genomic sequences of one or more intergenic regions,as well as SNP context sequences and other SNP information for any SNPsthat lie within these intergenic regions. Additionally, in either Table1 or 2 a “Related Interrogated SNP” may be listed following a SNP whichis determined to be in LD with that interrogated SNP according to thegiven Power value. SNPs can readily be cross-referenced between allTables based on their Celera hCV (or, in some instances, hDV)identification numbers, and to the Sequence Listing based on theircorresponding SEQ ID NOS.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in        the Table)    -   a Celera hCG and UID internal identification numbers for the        gene    -   a Celera hCT and UID internal identification numbers for the        transcript (Table 1 only)    -   a public Genbank accession number (e.g., RefSeq NM number) for        the transcript (Table 1 only)    -   a Celera hCP and UID internal identification numbers for the        protein encoded by the hCT transcript (Table 1 only)    -   a public Genbank accession number (e.g., RefSeq NP number) for        the protein (Table 1 only)    -   an art-known gene symbol    -   an art-known gene/protein name    -   Celera genomic axis position (indicating start nucleotide        position-stop nucleotide position)    -   the chromosome number of the chromosome on which the gene is        located    -   an OVTM (Online Mendelian Inheritance in Man; Johns Hopkins        University/NCBI) public reference number for obtaining further        information regarding the medical significance of each gene    -   alternative gene/protein name(s) and/or symbol(s) in the OVTEM        entry

Note that, due to the presence of alternative splice forms, multipletranscript/protein entries may be provided for a single gene entry inTable 1; i.e., for a single Gene Number, multiple entries may beprovided in series that differ in their transcript/protein informationand sequences.

Following the gene/transcript/protein information is a transcriptcontext sequence and (Table 1), or a genomic context sequence (Table 2),for each SNP within that gene.

After the last gene sequence, Table 2 may include additional genomicsequences of intergenic regions (in such instances, these sequences areidentified as “Intergenic region:” followed by a numericalidentification number), as well as SNP context sequences and other SNPinformation for any SNPs that lie within each intergenic region (suchSNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP contextsequences are all provided in the Sequence Listing. The transcript-basedSNP context sequences are provided in both Table 1 and also in theSequence Listing. The genomic and genomic-based SNP context sequencesare provided in the Sequence Listing. The genomic-based SNP contextsequences are provided in both Table 2 and in the Sequence Listing. SEQID NOS are indicated in Table 1 for the transcript-based contextsequences (SEQ ID NOS: 251-403); SEQ ID NOS are indicated in Table 2 forthe genomic-based context sequences (SEQ ID NOS: 602-1587).

The SNP information includes:

-   -   context sequence (taken from the transcript sequence in Table 1,        the genomic sequence in Table 2) with the SNP represented by its        IUB code, including 100 bp upstream (5′) of the SNP position        plus 100 bp downstream (3′) of the SNP position (the        transcript-based SNP context sequences in Table 1 are provided        in the Sequence Listing as SEQ ID NOS: 251-403; the        genomic-based SNP context sequences in Table 2 are provided in        the Sequence Listing as SEQ ID NOS: 602-1587).    -   Celera hCV internal identification number for the SNP (in some        instances, an “hDV” number is given instead of an “hCV” number).    -   The corresponding public identification number for the SNP, the        RS number.    -   SNP position (position of the SNP within the given transcript        sequence (Table 1) or within the given genomic sequence (Table        2)).    -   “Related Interrogated SNP” is as the interrogated SNP with which        the listed SNP is in LD at the given value of Power.    -   SNP source (may include any combination of one or more of the        following five codes, depending on which internal sequencing        projects and/or public databases the SNP has been observed in:        “Applera”=SNP observed during the re-sequencing of genes and        regulatory regions of 39 individuals, “Celera”=SNP observed        during shotgun sequencing and assembly of the Celera human        genome sequence, “Celera Diagnostics”=SNP observed during        re-sequencing of nucleic acid samples from individuals who have        a disease, “dbSNP”=SNP observed in the dbSNP public database,        “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP        observed in the Human Gene Mutation Database (HGMD) public        database, “HapMap”=SNP observed in the International HapMap        Project public database, “CSNP”=SNP observed in an internal        Applied Biosystems (Foster City, Calif.) database of coding SNPS        (cSNPs)). Note that multiple “Applera” source entries for a        single SNP indicate that the same SNP was covered by multiple        overlapping amplification products and the re-sequencing results        (e.g., observed allele counts) from each of these amplification        products is being provided.

For the following SNPs provided in Table 1 and/or Table 2, the SNPsource falls into one of the following three categories: 1) SNPs forwhich the SNP source is only “Applera” and none other, 2) SNPs for whichthe SNP source is only “Celera Diagnostics” and none other, and 3) SNPsfor which the SNP source is both “Applera” and “Celera Diagnostics” butnone other (the hCV identification number and SEQ ID NO for the SNP'sgenomic context sequence in Table 2 are indicated): hCV22275299 (SEQ IDNO:482), hCV25615822 (SEQ ID NO:639), hCV25651109 (SEQ ID NO:840),hCV25951678 (SEQ ID NO:1013), and hCV25615822 (SEQ ID NO:1375). TheseSNPs have not been observed in any of the public databases (dbSNP,HGBASE, and HGMD), and were also not observed during shotgun sequencingand assembly of the Celera human genome sequence (i.e., “Celera” SNPsource).

-   -   Population/allele/allele count information in the format of        [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count)total        (first_allele,total count|second_allele,total count)]. The        information in this field includes populations/ethnic groups in        which particular SNP alleles have been observed        (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and        “afr”=African-American, “jpn”=Japanese, “ind”=Indian,        “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,        “no_pop”=no population information available), identified SNP        alleles, and observed allele counts (within each population        group and total allele counts), where available [“−” in the        allele field represents a deletion allele of an        insertion/deletion (“indel”) polymorphism (in which case the        corresponding insertion allele, which may be comprised of one or        more nucleotides, is indicated in the allele field on the        opposite side of the “|”); “−” in the count field indicates that        allele count information is not available]. For certain SNPs        from the public dbSNP database, population/ethnic information is        indicated as follows (this population information is publicly        available in dbSNP): “HISP1”=human individual DNA (anonymized        samples) from 23 individuals of self-described HISPANIC        heritage; “PAC1”=human individual DNA (anonymized samples) from        24 individuals of self-described PACIFIC RIM heritage;        “CAUC1”=human individual DNA (anonymized samples) from 31        individuals of self-described CAUCASIAN heritage; “AFR1”=human        individual DNA (anonymized samples) from 24 individuals of        self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human        individual DNA (anonymized samples) from 102 individuals of        self-described heritage; “PA130299515”; “SC_(—)12_A”=SANGER 12        DNAs of Asian origin from Corielle cell repositories, 6 of which        are male and 6 female; “SC_(—)12_C”=SANGER 12 DNAs of Caucasian        origin from Corielle cell repositories from the CEPH/UTAH        library. Six male and 6 female; “SC_(—)12_AA”=SANGER 12 DNAs of        African-American origin from Corielle cell repositories 6 of        which are male and 6 female; “SC_(—)95_C”=SANGER 95 DNAs of        Caucasian origin from Corielle cell repositories from the        CEPH/UTAH library; and “SC_(—)12_CA”=Caucasians−12 DNAs from        Corielle cell repositories that are from the CEPH/UTAH library.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of39 individuals (20 Caucasians and 19 African Americans) werere-sequenced and, since each SNP position is represented by twochromosomes in each individual (with the exception of SNPs on X and Ychromosomes in males, for which each SNP position is represented by asingle chromosome), up to 78 chromosomes were genotyped for each SNPposition. Thus, the sum of the African-American (“afr”) allele counts isup to 38, the sum of the Caucasian allele counts (“cau”) is up to 40,and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count informationcorresponding to each indicated SNP source; i.e., if four SNP sourcesare indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” thenpopulation/allele/count information is provided in four groups which areseparated by semicolons and listed in the same order as the listing ofSNP sources, with each population/allele/count information groupcorresponding to the respective SNP source based on order; thus, in thisexample, the first population/allele/count information group wouldcorrespond to the first listed SNP source (Celera) and the thirdpopulation/allele/count information group separated by semicolons wouldcorrespond to the third listed SNP source (HGBASE); ifpopulation/allele/count information is not available for any particularSNP source, then a pair of semicolons is still inserted as aplace-holder in order to maintain correspondence between the list of SNPsources and the corresponding listing of population/allele/countinformation.

-   -   SNP type (e.g., location within gene/transcript and/or predicted        functional effect) [“VTES-SENSE MUTATION”=SNP causes a change in        the encoded amino acid (i.e., a non-synonymous coding SNP);        “SILENT MUTATION”=SNP does not cause a change in the encoded        amino acid (i.e., a synonymous coding SNP); “STOP CODON        MUTATION”=SNP is located in a stop codon; “NONSENSE        MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is        located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a        3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a        putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative        3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice        site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located        in an acceptor splice site (3′ intron boundary); “CODING        REGION”=SNP is located in a protein-coding region of the        transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is        located in an intron; “hmCS”=SNP is located in a human-mouse        conserved segment; “TFBS”=SNP is located in a transcription        factor binding site; “UNKNOWN”=SNP type is not defined;        “INTERGENIC”=SNP is intergenic, i.e., outside of any gene        boundary].    -   Protein coding information (Table 1 only), where relevant, in        the format of [protein SEQ ID NO: #, amino acid position, (amino        acid-1, codon1) (amino acid-2, codon2)]. The information in this        field includes SEQ ID NO of the encoded protein sequence,        position of the amino acid residue within the protein identified        by the SEQ ID NO that is encoded by the codon containing the        SNP, amino acids (represented by one-letter amino acid codes)        that are encoded by the alternative SNP alleles (in the case of        stop codons, “X” is used for the one-letter amino acid code),        and alternative codons containing the alternative SNP        nucleotides which encode the amino acid residues (thus, for        example, for missense mutation-type SNPs, at least two different        amino acids and at least two different codons are generally        indicated; for silent mutation-type SNPs, one amino acid and at        least two different codons are generally indicated, etc.). In        instances where the SNP is located outside of a protein-coding        region (e.g., in a UTR region), “None” is indicated following        the protein SEQ ID NO.

Description of Table 3

Table 3 provides sequences (SEQ ID NOS: 1588-2556) of oligonucleotidesthat have been synthesized and used in the laboratory to assay the SNPsdisclosed in Tables 5-13 during the course of association studies toverify the association of these SNPs with VT. The experiments that wereconducted using these primers are explained in detail in Example 1,below.

Table 3 provides the following:

-   -   the column labeled “Marker” lists the Celera identifier hCV        number for each SNP marker.    -   the column labeled “Alleles” designates the two alternative        alleles at the SNP site identified by the hCV identification        number that are targeted by the allele-specific        oligonucleotides.    -   allele-specific oligonucleotides with their respective SEQ ID        numbers are shown in the next two columns, “Sequence A        (allele-specific primer)” and “Sequence B (allele-specific        primer).” These two primers were used in conjunction with a        common primer in each PCR assay to genotype DNA samples for each        SNP marker. Note that alleles may be presented in Table 3 based        on a different orientation (i.e., the reverse complement)        relative to how the same alleles are presented in Tables 1 and        2.    -   common oligonucleotides with their respective SEQ ID numbers are        shown in the column, “Sequence C (common primer).” Each common        primer was used in conjunction with the two allele-specific        primers to genotype DNA samples for each SNP marker.

All sequences are given in the 5′ to 3′ direction.

Description of Table 4

Table 4 provides a list of the sample LD SNPs that are related to andderived from an interrogated SNP. These LD SNPs are provided as anexample of the groups of SNPs which can also serve as markers fordisease association based on their being in LD with the interrogatedSNP. The criteria and process of selecting such LD SNPs, including thecalculation of the r² value and the r² threshold value, are described inExample Ten, below.

In Table 4, the column labeled “Interrogated SNP” presents each markeras identified by its unique identifier, the hCV number. The columnlabeled “Interrogated rs” presents the publicly known identifier rsnumber for the corresponding hCV number. The column labeled “LD SNP”presents the hCV numbers of the LD SNPs that are derived from theircorresponding interrogated SNPs. The column labeled “LD SNP rs” presentsthe publicly known rs number for the corresponding hCV number. Thecolumn labeled “Power (T)” presents the level of power where the r²threshold is set. For example, when power is set at 51%, the thresholdr² value calculated therefrom is the minimum r² that an LD SNP must havein reference to an interrogated SNP, in order for the LD SNP to beclassified as a marker capable of being associated with a diseasephenotype at greater than 51% probability. The column labeled “Thresholdr_(T) ²” presents the minimum value of r² that an LD SNP must meet inreference to an interrogated SNP in order to qualify as an LD SNP. Thecolumn labeled “r²” presents the actual r² value of the LD SNP inreference to the interrogated SNP to which it is related.

Description of Other Tables

Tables 3-4, 20-23, and 25-27 are provided following the Examples section(before the claims) of the instant specification. Tables 1-2 areprovided as separate ASCII text files. Tables 1-4 are described above.Tables 5-19, 24, and 28-29 are provided within the Examples section ofthe instant specification below and are described there. Thus, thissection describes Tables 20-23 and 25-27.

Table 20 provides unadjusted additive and genotypic association with DVTfor 149 SNPs that were tested in both MEGA-1 and LETS, and wereassociated with DVT in both of these sample sets (p-value cutoff <=0.05in MEGA-1 and p-value cutoff <=0.1 in LETS, in at least one model).

Table 21 provides unadjusted association of 92 SNPs with DVT in LETS(p<=0.05) that have not yet been tested in the MEGA-1 sample set.

Table 22 provides unadjusted association of 9 SNPs with DVT in MEGA-1(p<=0.05) that have not yet been tested in the LETS sample set.

Table 23 provides age- and sex-adjusted association with DVT for 41 SNPsthat were tested in the three sample sets LETS, MEGA-1, and MEGA-2.

See Example Five below regarding Tables 20-23.

Table 25 provides age- and sex-adjusted association with isolatedpulmonary embolism (PE) for 52 SNPs in MEGA-1 and MEGA-2 combined(p-value cutoff <=0.05). See Example Seven below.

Table 26 provides age- and sex-adjusted association with cancer-relatedDVT for 31 SNPs in MEGA-1 and MEGA-2 combined (p-value cutoff <=0.05).The SNPs provided in Table 26 had a p-value cutoff <=0.05 when comparingindividuals (cases) in the MEGA-1 and MEGA-2 studies who had both cancer(of any type) and DVT compared with individuals (controls) who hadneither cancer nor DVT. See Example Eight below.

Table 27 provides additive association with DVT for 123 SNPs in LETS(p-value cutoff <=0.1 in LETS). Linkage disequilibrium data from Hapmapis also provided for each SNP. The SNPs in Table 27 are based onfine-mapping/linkage disequilibrium analysis around the following targetgenes and SNPs (as indicated in Table 27): gene AKT3 (SNP hCV233148),gene SERPINC1 (SNP hCV16180170), gene RGS7 (SNP hCV916107), gene NR1I2(SNP hCV263841), gene FGG (SNP hCV11503469), gene CYP4V2 (SNPhCV25990131), gene GP6 (SNP hCV8717873), and gene F9 (SNP hCV596331).See Example Nine below.

The following abbreviations may be used throughout the tables:“cnt”=count, “frq”=frequency, “dom”=dominant, “rec”=recessive,“gen”=genotypic, “add”=additive, “annot”=annotation (description),“genot”=genotype, and “Control RAF”=risk allele frequency in controls.

Throughout the tables, “HR” or “HRR” refers to the hazard ratio, “OR”refers to the odds ratio, terms such as “90% CI” or “95% CI” refer tothe 90% or 95% confidence interval (respectively) for the hazard ratioor odds ratio, and terms such as “OR95l” and “OR95u” refer to the lowerand upper 95% confidence intervals (respectively) for the odds ratio(“CI”/“confidence interval” and “CL”/“confidence limit” may be usedherein interchangeably). Hazard ratios (“HR” or “HRR”) or odds ratios(OR) that are greater than one indicate that a given allele (orcombination of alleles such as a haplotype or diplotype) is a riskallele (which may also be referred to as a susceptibility allele),whereas hazard ratios or odds ratios that are less than one indicatethat a given allele is a non-risk allele (which may also be referred toas a protective allele). For a given risk allele, the other alternativeallele at the SNP position (which can be derived from the informationprovided in Tables 1-2, for example) may be considered a non-riskallele. For a given non-risk allele, the other alternative allele at theSNP position may be considered a risk allele.

Thus, with respect to disease risk (e.g., VT), if the risk estimate(odds ratio or hazard ratio) for a particular allele at a SNP positionis greater than one, this indicates that an individual with thisparticular allele has a higher risk for the disease than an individualwho has the other allele at the SNP position. In contrast, if the riskestimate (odds ratio or hazard ratio) for a particular allele is lessthan one, this indicates that an individual with this particular allelehas a reduced risk for the disease compared with an individual who hasthe other allele at the SNP position.

DESCRIPTION OF THE FIGURES

FIG. 1 shows a flowchart of the approach used to identify SNPsassociated with DVT. On the left, the “IN” box indicates the number ofSNPs genotyped in each stage. On the right, the “OUT” box indicates thenumber of SNPs associated with DVT in each stage (P<0.05). To conserveMEGA-2 DNA in Stage 4, SNPs were genotyped using multiplexed oligoligation assays, and assays for only 9 of the 18 Stage 3 SNPs wereavailable in multiplex format at the time of this study.

FIG. 2 shows the meta-analysis of Factor IX Malmö with DVT in women andmen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with VT, nucleic acidmolecules containing SNPs, methods and reagents for the detection of theSNPs disclosed herein, uses of these SNPs for the development ofdetection reagents, and assays or kits that utilize such reagents. TheVT-associated SNPs disclosed herein are useful for diagnosing, screeningfor, and evaluating predisposition to VT and related pathologies inhumans. Furthermore, such SNPs and their encoded products are usefultargets for the development of therapeutic agents.

A large number of SNPs have been identified from re-sequencing DNA from39 individuals, and they are indicated as “Applera” SNP source in Tables1-2. Their allele frequencies observed in each of the Caucasian andAfrican-American ethnic groups are provided. Additional SNPs includedherein were previously identified during shotgun sequencing and assemblyof the human genome, and they are indicated as “Celera” SNP source inTables 1-2. Furthermore, the information provided in Table 1-2,particularly the allele frequency information obtained from 39individuals and the identification of the precise position of each SNPwithin each gene/transcript, allows haplotypes (i.e., groups of SNPsthat are co-inherited) to be readily inferred. The present inventionencompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated with VT,as well as combinations of SNPs and haplotypes in genetic regionsassociated with VT, polymorphic/variant transcript sequences (SEQ IDNOS: 1-125) and genomic sequences (SEQ ID NOS: 404-601) containing SNPs,encoded amino acid sequences (SEQ ID NOS: 126-250), and bothtranscript-based SNP context sequences (SEQ ID NOS: 251-403) andgenomic-based SNP context sequences (SEQ ID NOS: 602-1587) (transcriptsequences, protein sequences, and transcript-based SNP context sequencesare provided in Table 1 and the Sequence Listing; genomic sequences andgenomic-based SNP context sequences are provided in Table 2 and theSequence Listing), methods of detecting these polymorphisms in a testsample, methods of determining the risk of an individual of having ordeveloping VT, methods of screening for compounds useful for treatingdisorders associated with a variant gene/protein such as VT, compoundsidentified by these screening methods, methods of using the disclosedSNPs to select a treatment strategy, methods of treating a disorderassociated with a variant gene/protein (i.e., therapeutic methods),methods of determining if an individual is likely to respond to aspecific treatment and methods of using the SNPs of the presentinvention for human identification.

The present invention provides novel SNPs associated with VT, as well asSNPs that were previously known in the art, but were not previouslyknown to be associated with VT. Accordingly, the present inventionprovides novel compositions and methods based on the novel SNPsdisclosed herein, and also provides novel methods of using the known,but previously unassociated, SNPs in methods relating to VT (e.g., fordiagnosing VT, etc.). In Tables 1-2, known SNPs are identified based onthe public database in which they have been observed, which is indicatedas one or more of the following SNP types: “dbSNP”=SNP observed indbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in theHuman Gene Mutation Database (HGMD). Novel SNPs for which the SNP sourceis only “Applera” and none other, i.e., those that have not beenobserved in any public databases and which were also not observed duringshotgun sequencing and assembly of the Celera human genome sequence(i.e., “Celera” SNP source), are also noted in the tables.

Particular SNP alleles of the present invention can be associated witheither an increased risk of having or developing VT, or a decreased riskof having or developing VT. SNP alleles that are associated with adecreased risk of having or developing VT may be referred to as“protective” alleles, and SNP alleles that are associated with anincreased risk of having or developing VT may be referred to as“susceptibility” alleles, “risk” alleles, or “risk factors”. Thus,whereas certain SNPs (or their encoded products) can be assayed todetermine whether an individual possesses a SNP allele that isindicative of an increased risk of having or developing VT (i.e., asusceptibility allele), other SNPs (or their encoded products) can beassayed to determine whether an individual possesses a SNP allele thatis indicative of a decreased risk of having or developing VT (i.e., aprotective allele). Similarly, particular SNP alleles of the presentinvention can be associated with either an increased or decreasedlikelihood of responding to a particular treatment or therapeuticcompound, or an increased or decreased likelihood of experiencing toxiceffects from a particular treatment or therapeutic compound. The term“altered” may be used herein to encompass either of these twopossibilities (e.g., an increased or a decreased risk/likelihood).

Those skilled in the art will readily recognize that nucleic acidmolecules may be double-stranded molecules and that reference to aparticular site on one strand refers, as well, to the corresponding siteon a complementary strand. In defining a SNP position, SNP allele, ornucleotide sequence, reference to an adenine, a thymine (uridine), acytosine, or a guanine at a particular site on one strand of a nucleicacid molecule also defines the thymine (uridine), adenine, guanine, orcytosine (respectively) at the corresponding site on a complementarystrand of the nucleic acid molecule. Thus, reference may be made toeither strand in order to refer to a particular SNP position, SNPallele, or nucleotide sequence. Probes and primers, may be designed tohybridize to either strand and SNP genotyping methods disclosed hereinmay generally target either strand. Throughout the specification, inidentifying a SNP position, reference is generally made to theprotein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the presentinvention include peptides, polypeptides, proteins, or fragmentsthereof, that contain at least one amino acid residue that differs fromthe corresponding amino acid sequence of the art-knownpeptide/polypeptide/protein (the art-known protein may beinterchangeably referred to as the “wild-type,” “reference,” or “normal”protein). Such variant peptides/polypeptides/proteins can result from acodon change caused by a nonsynonymous nucleotide substitution at aprotein-coding SNP position (i.e., a missense mutation) disclosed by thepresent invention. Variant peptides/polypeptides/proteins of the presentinvention can also result from a nonsense mutation, i.e., a SNP thatcreates a premature stop codon, a SNP that generates a read-throughmutation by abolishing a stop codon, or due to any SNP disclosed by thepresent invention that otherwise alters the structure,function/activity, or expression of a protein, such as a SNP in aregulatory region (e.g. a promoter or enhancer) or a SNP that leads toalternative or defective splicing, such as a SNP in an intron or a SNPat an exon/intron boundary. As used herein, the terms “polypeptide,”“peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position(wherein at least two alternative nucleotides exist in the population atthe SNP position, in accordance with the inherent definition of a SNP)or may refer to an amino acid residue that is encoded by the codon whichcontains the SNP position (where the alternative nucleotides that arepresent in the population at the SNP position form alternative codonsthat encode different amino acid residues). An “allele” may also bereferred to herein as a “variant”. Also, an amino acid residue that isencoded by a codon containing a particular SNP may simply be referred toas being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”,or “as designated by” may be used herein to refer to a SNP within asequence (e.g., a polynucleotide context sequence surrounding a SNP),such as in the context of “a polymorphism as represented by position 101of SEQ ID NO:X or its complement”. Typically, the sequence surrounding aSNP may be recited when referring to a SNP, however the sequence is notintended as a structural limitation beyond the specific SNP positionitself. Rather, the sequence is recited merely as a way of referring tothe SNP (in this example, “SEQ ID NO:X or its complement” is recited inorder to refer to the SNP located at position 101 of SEQ ID NO:X, butSEQ ID NO:X or its complement is not intended as a structural limitationbeyond the specific SNP position itself). A SNP is a variation at asingle nucleotide position and therefore it is customary to refer tocontext sequence (e.g., SEQ ID NO:X in this example) surrounding aparticular SNP position in order to uniquely identify and refer to theSNP. Alternatively, a SNP can be referred to by a unique identificationnumber such as a public “rs” identification number or an internal “hCV”identification number, such as provided herein for each SNP (e.g., inTables 1-2).

With respect to an individual's risk for a disease (e.g., based on thepresence or absence of one or more SNPs disclosed herein in theindividual's nucleic acid), terms such as “assigning” or “designating”may be used herein to characterize the individual's risk for thedisease.

As used herein, the term “benefit” (with respect to a preventive ortherapeutic drug treatment) is defined as achieving a reduced risk for adisease that the drug is intended to treat or prevent (e.g., VT) byadministrating the drug treatment, compared with the risk for thedisease in the absence of receiving the drug treatment (or receiving aplacebo in lieu of the drug treatment) for the same genotype. The term“benefit” may be used herein interchangeably with terms such as “respondpositively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably, and may include, but are not limited to, small moleculecompounds, biologics (e.g., antibodies, proteins, protein fragments,fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g.,antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc.,which may be used for therapeutic and/or preventive treatment of adisease (e.g., VT).

The various methods described herein, such as correlating the presenceor absence of a polymorphism with an altered (e.g., increased ordecreased) risk (or no altered risk) for VT, can be carried out byautomated methods such as by using a computer (or otherapparatus/devices such as biomedical devices, laboratoryinstrumentation, or other apparatus/devices having a computer processor)programmed to carry out any of the methods described herein. Forexample, computer software (which may be interchangeably referred toherein as a computer program) can perform the step of correlating thepresence or absence of a polymorphism in an individual with an altered(e.g., increased or decreased) risk (or no altered risk) for VT for theindividual. Computer software can also perform the step of correlatingthe presence or absence of a polymorphism in an individual with thepredicted response of the individual to a therapeutic agent or othertype of treatment. Accordingly, certain embodiments of the inventionprovide a computer (or other apparatus/device) programmed to carry outany of the methods described herein.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for VT, or anindividual's predicted drug responsiveness, based on assaying one ormore SNPs disclosed herein, and/or an individual's allele(s)/genotype atone or more SNPs disclosed herein, etc.), and/or any other informationpertaining to a test, may be referred to herein as a “report”. Atangible report can optionally be generated as part of a testing process(which may be interchangeably referred to herein as “reporting”, or as“providing” a report, “producing” a report, or “generating” a report).

Examples of tangible reports may include, but are not limited to,reports in paper (such as computer-generated printouts of test results)or equivalent formats and reports stored on computer readable medium(such as a CD, USB flash drive or other removable storage device,computer hard drive, or computer network server, etc.). Reports,particularly those stored on computer readable medium, can be part of adatabase, which may optionally be accessible via the internet (such as adatabase of patient records or genetic information stored on a computernetwork server, which may be a “secure database” that has securityfeatures that limit access to the report, such as to allow only thepatient and the patient's medical practioners to view the report whilepreventing other unauthorized individuals from viewing the report, forexample). In addition to, or as an alternative to, generating a tangiblereport, reports can also be displayed on a computer screen (or thedisplay of another electronic device or instrument).

A report can include, for example, an individual's risk for VT, or mayjust include the allele(s)/genotype that an individual carries at one ormore SNPs disclosed herein, which may optionally be linked toinformation regarding the significance of having the allele(s)/genotypeat the SNP (for example, a report on computer readable medium such as anetwork server may include hyperlink(s) to one or more journalpublications or websites that describe the medical/biologicalimplications, such as increased or decreased disease risk, forindividuals having a certain allele/genotype at the SNP). Thus, forexample, the report can include disease risk or other medical/biologicalsignificance (e.g., drug responsiveness, etc.) as well as optionallyalso including the allele/genotype information, or the report may justinclude allele/genotype information without including disease risk orother medical/biological significance (such that an individual viewingthe report can use the allele/genotype information to determine theassociated disease risk or other medical/biological significance from asource outside of the report itself, such as from a medical practioner,publication, website, etc., which may optionally be linked to the reportsuch as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms maybe used herein interchangeably), such as to the individual who wastested, a medical practitioner (e.g., a doctor, nurse, clinicallaboratory practitioner, genetic counselor, etc.), a healthcareorganization, a clinical laboratory, and/or any other party or requesterintended to view or possess the report. The act of “transmitting” or“communicating” a report can be by any means known in the art, based onthe format of the report. Furthermore, “transmitting” or “communicating”a report can include delivering a report (“pushing”) and/or retrieving(“pulling”) a report. For example, reports can betransmitted/communicated by various means, including being physicallytransferred between parties (such as for reports in paper format) suchas by being physically delivered from one party to another, or by beingtransmitted electronically or in signal form (e.g., via e-mail or overthe internet, by facsimile, and/or by any wired or wirelesscommunication methods known in the art) such as by being retrieved froma database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (orother apparatus/devices such as biomedical devices or laboratoryinstrumentation) programmed to carry out the methods described herein.For example, in certain embodiments, the invention provides a computerprogrammed to receive (i.e., as input) the identity (e.g., the allele(s)or genotype at a SNP) of one or more SNPs disclosed herein and provide(i.e., as output) the disease risk (e.g., an individual's risk for VT)or other result (e.g., disease diagnosis or prognosis, drugresponsiveness, etc.) based on the identity of the SNP(s). Such output(e.g., communication of disease risk, disease diagnosis or prognosis,drug responsiveness, etc.) may be, for example, in the form of a reporton computer readable medium, printed in paper form, and/or displayed ona computer screen or other display.

In various exemplary embodiments, the invention further provides methodsof doing business (with respect to methods of doing business, the terms“individual” and “customer” are used herein interchangeably). Forexample, exemplary methods of doing business can comprise assaying oneor more SNPs disclosed herein and providing a report that includes, forexample, a customer's risk for VT (based on which allele(s)/genotype ispresent at the assayed SNP(s)) and/or that includes theallele(s)/genotype at the assayed SNP(s) which may optionally be linkedto information (e.g., journal publications, websites, etc.) pertainingto disease risk or other biological/medical significance such as bymeans of a hyperlink (the report may be provided, for example, on acomputer network server or other computer readable medium that isinternet-accessible, and the report may be included in a secure databasethat allows the customer to access their report while preventing otherunauthorized individuals from viewing the report), and optionallytransmitting the report. Customers (or another party who is associatedwith the customer, such as the customer's doctor, for example) canrequest/order (e.g., purchase) the test online via the internet (or byphone, mail order, at an outlet/store, etc.), for example, and a kit canbe sent/delivered (or otherwise provided) to the customer (or anotherparty on behalf of the customer, such as the customer's doctor, forexample) for collection of a biological sample from the customer (e.g.,a buccal swab for collecting buccal cells), and the customer (or a partywho collects the customer's biological sample) can submit theirbiological samples for assaying (e.g., to a laboratory or partyassociated with the laboratory such as a party that accepts the customersamples on behalf of the laboratory, a party for whom the laboratory isunder the control of (e.g., the laboratory carries out the assays byrequest of the party or under a contract with the party, for example),and/or a party that receives at least a portion of the customer'spayment for the test). The report (e.g., results of the assay including,for example, the customer's disease risk and/or allele(s)/genotype atthe assayed SNP(s)) may be provided to the customer by, for example, thelaboratory that assays the SNP(s) or a party associated with thelaboratory (e.g., a party that receives at least a portion of thecustomer's payment for the assay, or a party that requests thelaboratory to carry out the assays or that contracts with the laboratoryfor the assays to be carried out) or a doctor or other medicalpractitioner who is associated with (e.g., employed by or having aconsulting or contracting arrangement with) the laboratory or with aparty associated with the laboratory, or the report may be provided to athird party (e.g., a doctor, genetic counselor, hospital, etc.) whichoptionally provides the report to the customer. In further embodiments,the customer may be a doctor or other medical practitioner, or ahospital, laboratory, medical insurance organization, or other medicalorganization that requests/orders (e.g., purchases) tests for thepurposes of having other individuals (e.g., their patients or customers)assayed for one or more SNPs disclosed herein and optionally obtaining areport of the assay results.

In certain exemplary methods of doing business, kits for collecting abiological sample from a customer (e.g., a buccal swab for collectingbuccal cells) are provided (e.g., for sale), such as at an outlet (e.g.,a drug store, pharmacy, general merchandise store, or any otherdesirable outlet), online via the internet, by mail order, etc., wherebycustomers can obtain (e.g., purchase) the kits, collect their ownbiological samples, and submit (e.g., send/deliver via mail) theirsamples to a laboratory which assays the samples for one or more SNPsdisclosed herein (such as to determine the customer's risk for VT) andoptionally provides a report to the customer (of the customer's diseaserisk based on their SNP genotype(s), for example) or provides theresults of the assay to another party (e.g., a doctor, geneticcounselor, hospital, etc.) which optionally provides a report to thecustomer (of the customer's disease risk based on their SNP genotype(s),for example).

Certain further embodiments of the invention provide a system fordetermining an individual's DVT risk, or whether an individual willbenefit from a drug treatment (or other therapy) in reducing DVT risk.Certain exemplary systems comprise an integrated “loop” in which anindividual (or their medical practitioner) requests a determination ofsuch individual's VT risk (or drug response, etc.), this determinationis carried out by testing a sample from the individual, and then theresults of this determination are provided back to the requester. Forexample, in certain systems, a sample (e.g., blood or buccal cells) isobtained from an individual for testing (the sample may be obtained bythe individual or, for example, by a medical practitioner), the sampleis submitted to a laboratory (or other facility) for testing (e.g.,determining the genotype of one or more SNPs disclosed herein), and thenthe results of the testing are sent to the patient (which optionally canbe done by first sending the results to an intermediary, such as amedical practioner, who then provides or otherwise conveys the resultsto the individual and/or acts on the results), thereby forming anintegrated loop system for determining an individual's DVT risk (or drugresponse, etc.). The portions of the system in which the results aretransmitted (e.g., between any of a testing facility, a medicalpractitioner, and/or the individual) can be carried out by way ofelectronic or signal transmission (e.g., by computer such as via e-mailor the internet, by providing the results on a website or computernetwork server which may optionally be a secure database, by phone orfax, or by any other wired or wireless transmission methods known in theart). Optionally, the system can further include a risk reductioncomponent (i.e., a disease management system) as part of the integratedloop (for an example of a disease management system, see U.S. Pat. No.6,770,029, “Disease management system and method including correlationassessment”). For example, the results of the test can be used to reducethe risk of the disease in the individual who was tested, such as byimplementing a preventive therapy regimen (e.g., administration of adrug regimen such as an anticoagulant and/or antiplatelet agent forreducing DVT risk), modifying the individual's diet, increasingexercise, reducing stress, and/or implementing any other physiologicalor behavioral modifications in the individual with the goal of reducingdisease risk. For reducing DVT risk, this may include any means used inthe art for improving cardiovascular health. Thus, in exemplaryembodiments, the system is controlled by the individual and/or theirmedical practioner in that the individual and/or their medicalpractioner requests the test, receives the test results back, and(optionally) acts on the test results to reduce the individual's diseaserisk, such as by implementing a disease management component.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of thepresent invention that is associated with VT, including the transcriptsequences (SEQ ID NOS: 1-125), genomic sequences (SEQ ID NOS: 404-601),and protein sequences (SEQ ID NOS: 126-250) of the encoded gene products(with the SNPs indicated by IUB codes in the nucleic acid sequences). Inaddition, Tables 1 and 2 include SNP context sequences, which generallyinclude 100 nucleotide upstream (5′) plus 100 nucleotides downstream(3′) of each SNP position (SEQ ID NOS: 251-403 correspond totranscript-based SNP context sequences disclosed in Table 1, and SEQ IDNOS: 602-1587 correspond to genomic-based context sequences disclosed inTable 2), the alternative nucleotides (alleles) at each SNP position,and additional information about the variant where relevant, such as SNPtype (coding, missense, splice site, UTR, etc.), human populations inwhich the SNP was observed, observed allele frequencies, informationabout the encoded protein, etc.

Isolated Nucleic Acid Molecules The present invention provides isolatednucleic acid molecules that contain one or more SNPs disclosed Table 1and/or Table 2. Isolated nucleic acid molecules containing one or moreSNPs disclosed in at least one of Tables 1-2 may be interchangeablyreferred to throughout the present text as “SNP-containing nucleic acidmolecules”. Isolated nucleic acid molecules may optionally encode afull-length variant protein or fragment thereof. The isolated nucleicacid molecules of the present invention also include probes and primers(which are described in greater detail below in the section entitled“SNP Detection Reagents”), which may be used for assaying the disclosedSNPs, and isolated full-length genes, transcripts, cDNA molecules, andfragments thereof, which may be used for such purposes as expressing anencoded protein.

As used herein, an “isolated nucleic acid molecule” generally is onethat contains a SNP of the present invention or one that hybridizes tosuch molecule such as a nucleic acid with a complementary sequence, andis separated from most other nucleic acids present in the natural sourceof the nucleic acid molecule. Moreover, an “isolated” nucleic acidmolecule, such as a cDNA molecule containing a SNP of the presentinvention, can be substantially free of other cellular material, orculture medium when produced by recombinant techniques, or chemicalprecursors or other chemicals when chemically synthesized. A nucleicacid molecule can be fused to other coding or regulatory sequences andstill be considered “isolated”. Nucleic acid molecules present innon-human transgenic animals, which do not naturally occur in theanimal, are also considered “isolated”. For example, recombinant DNAmolecules contained in a vector are considered “isolated”. Furtherexamples of “isolated” DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells, and purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the isolated SNP-containing DNAmolecules of the present invention. Isolated nucleic acid moleculesaccording to the present invention further include such moleculesproduced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprisesone or more SNP positions disclosed by the present invention withflanking nucleotide sequences on either side of the SNP positions. Aflanking sequence can include nucleotide residues that are naturallyassociated with the SNP site and/or heterologous nucleotide sequences.Preferably the flanking sequence is up to about 500, 300, 100, 60, 50,30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between)on either side of a SNP position, or as long as the full-length gene orentire protein-coding sequence (or any portion thereof such as an exon),especially if the SNP-containing nucleic acid molecule is to be used toproduce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNPflanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2KB, 1 KB on either side of the SNP. Furthermore, in such instances, theisolated nucleic acid molecule comprises exonic sequences (includingprotein-coding and/or non-coding exonic sequences), but may also includeintronic sequences. Thus, any protein coding sequence may be eithercontiguous or separated by introns. The important point is that thenucleic acid is isolated from remote and unimportant flanking sequencesand is of appropriate length such that it can be subjected to thespecific manipulations or uses described herein such as recombinantprotein expression, preparation of probes and primers for assaying theSNP position, and other uses specific to the SNP-containing nucleic acidsequences.

An isolated SNP-containing nucleic acid molecule can comprise, forexample, a full-length gene or transcript, such as a gene isolated fromgenomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, oran mRNA transcript molecule. Polymorphic transcript sequences arereferred to in Table 1 and provided in the Sequence Listing (SEQ ID NOS:1-125), and polymorphic genomic sequences are referred to in Table 2 andprovided in the Sequence Listing (SEQ ID NOS: 404-601). Furthermore,fragments of such full-length genes and transcripts that contain one ormore SNPs disclosed herein are also encompassed by the presentinvention, and such fragments may be used, for example, to express anypart of a protein, such as a particular functional domain or anantigenic epitope.

Thus, the present invention also encompasses fragments of the nucleicacid sequences as disclosed in Tables 1-2 (transcript sequences arereferred to in Table 1 as SEQ ID NOS: 1-125, genomic sequences arereferred to in Table 2 as SEQ ID NOS: 404-601, transcript-based SNPcontext sequences are referred to in Table 1 as SEQ ID NO: 251-403, andgenomic-based SNP context sequences are referred to in Table 2 as SEQ IDNO: 602-1587) and their complements. The actual sequences referred to inthe tables are provided in the Sequence Listing. A fragment typicallycomprises a contiguous nucleotide sequence at least about 8 or morenucleotides, more preferably at least about 12 or more nucleotides, andeven more preferably at least about 16 or more nucleotides. Further, afragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60,80, 100, 150, 200, 250 or 500 (or any other number in-between)nucleotides in length. The length of the fragment will be based on itsintended use. For example, the fragment can encode epitope-bearingregions of a variant peptide or regions of a variant peptide that differfrom the normal/wild-type protein, or can be useful as a polynucleotideprobe or primer. Such fragments can be isolated using the nucleotidesequences provided in Table 1 and/or Table 2 for the synthesis of apolynucleotide probe. A labeled probe can then be used, for example, toscreen a cDNA library, genomic DNA library, or mRNA to isolate nucleicacid corresponding to the coding region. Further, primers can be used inamplification reactions, such as for purposes of assaying one or moreSNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention furtherencompasses a SNP-containing polynucleotide that is the product of anyone of a variety of nucleic acid amplification methods, which are usedto increase the copy numbers of a polynucleotide of interest in anucleic acid sample. Such amplification methods are well known in theart, and they include but are not limited to, polymerase chain reaction(PCR) (U.S. Pat. Nos. 4,683,195; and 4,683,202; PCR Technology:Principles and Applications for DNA Amplification, ed. H. A. Erlich,Freeman Press, NY, N.Y., 1992), ligase chain reaction (LCR) (Wu andWallace, Genomics 4:560, 1989; Landegren et al., Science 241:1077,1988), strand displacement amplification (SDA) (U.S. Pat. Nos.5,270,184; and 5,422,252), transcription-mediated amplification (TMA)(U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat.No. 6,027,923), and the like, and isothermal amplification methods suchas nucleic acid sequence based amplification (NASBA), and self-sustainedsequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87:1874, 1990). Based on such methodologies, a person skilled in the artcan readily design primers in any suitable regions 5′ and 3′ to a SNPdisclosed herein. Such primers may be used to amplify DNA of any lengthso long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is aSNP-containing nucleic acid molecule whose amount has been increased atleast two fold by any nucleic acid amplification method performed invitro as compared to its starting amount in a test sample. In otherpreferred embodiments, an amplified polynucleotide is the result of atleast ten fold, fifty fold, one hundred fold, one thousand fold, or eventen thousand fold increase as compared to its starting amount in a testsample. In a typical PCR amplification, a polynucleotide of interest isoften amplified at least fifty thousand fold in amount over theunamplified genomic DNA, but the precise amount of amplification neededfor an assay depends on the sensitivity of the subsequent detectionmethod used.

Generally, an amplified polynucleotide is at least about 16 nucleotidesin length. More typically, an amplified polynucleotide is at least about20 nucleotides in length. In a preferred embodiment of the invention, anamplified polynucleotide is at least about 30 nucleotides in length. Ina more preferred embodiment of the invention, an amplifiedpolynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides inlength. In yet another preferred embodiment of the invention, anamplified polynucleotide is at least about 100, 200, 300, 400, or 500nucleotides in length. While the total length of an amplifiedpolynucleotide of the invention can be as long as an exon, an intron orthe entire gene where the SNP of interest resides, an amplified productis typically up to about 1,000 nucleotides in length (although certainamplification methods may generate amplified products greater than 1000nucleotides in length). More preferably, an amplified polynucleotide isnot greater than about 600-700 nucleotides in length. It is understoodthat irrespective of the length of an amplified polynucleotide, a SNP ofinterest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is atleast about 201 nucleotides in length, comprises one of thetranscript-based context sequences or the genomic-based contextsequences shown in Tables 1-2. Such a product may have additionalsequences on its 5′ end or 3′ end or both. In another embodiment, theamplified product is about 101 nucleotides in length, and it contains aSNP disclosed herein. Preferably, the SNP is located at the middle ofthe amplified product (e.g., at position 101 in an amplified productthat is 201 nucleotides in length, or at position 51 in an amplifiedproduct that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplifiedproduct (however, as indicated above, the SNP of interest may be locatedanywhere along the length of the amplified product).

The present invention provides isolated nucleic acid molecules thatcomprise, consist of, or consist essentially of one or morepolynucleotide sequences that contain one or more SNPs disclosed herein,complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules thatconsist of any of the nucleotide sequences shown in Table 1 and/or Table2 (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-125,genomic sequences are referred to in Table 2 as SEQ ID NOS: 404-601,transcript-based SNP context sequences are referred to in Table 1 as SEQID NO: 251-403, and genomic-based SNP context sequences are referred toin Table 2 as SEQ ID NO: 602-1587), or any nucleic acid molecule thatencodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:126-250). The actual sequences referred to in the tables are provided inthe Sequence Listing. A nucleic acid molecule consists of a nucleotidesequence when the nucleotide sequence is the complete nucleotidesequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules thatconsist essentially of any of the nucleotide sequences referred to inTable 1 and/or Table 2 (transcript sequences are referred to in Table 1as SEQ ID NOS: 1-125, genomic sequences are referred to in Table 2 asSEQ ID NOS: 404-601, transcript-based SNP context sequences are referredto in Table 1 as SEQ ID NO: 251-403, and genomic-based SNP contextsequences are referred to in Table 2 as SEQ ID NO: 602-1587), or anynucleic acid molecule that encodes any of the variant proteins referredto in Table 1 (SEQ ID NOS: 126-250). The actual sequences referred to inthe tables are provided in the Sequence Listing. A nucleic acid moleculeconsists essentially of a nucleotide sequence when such a nucleotidesequence is present with only a few additional nucleotide residues inthe final nucleic acid molecule.

The present invention further provides nucleic acid molecules thatcomprise any of the nucleotide sequences shown in Table 1 and/or Table 2or a SNP-containing fragment thereof (transcript sequences are referredto in Table 1 as SEQ ID NOS: 1-125, genomic sequences are referred to inTable 2 as SEQ ID NOS: 404-601, transcript-based SNP context sequencesare referred to in Table 1 as SEQ ID NO: 251-403, and genomic-based SNPcontext sequences are referred to in Table 2 as SEQ ID NO: 602-1587), orany nucleic acid molecule that encodes any of the variant proteinsprovided in Table 1 (SEQ ID NOS: 126-250). The actual sequences referredto in the tables are provided in the Sequence Listing. A nucleic acidmolecule comprises a nucleotide sequence when the nucleotide sequence isat least part of the final nucleotide sequence of the nucleic acidmolecule. In such a fashion, the nucleic acid molecule can be only thenucleotide sequence or have additional nucleotide residues, such asresidues that are naturally associated with it or heterologousnucleotide sequences. Such a nucleic acid molecule can have one to a fewadditional nucleotides or can comprise many more additional nucleotides.A brief description of how various types of these nucleic acid moleculescan be readily made and isolated is provided below, and such techniquesare well known to those of ordinary skill in the art (Sambrook andRussell, 2000, Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Press, NY).

The isolated nucleic acid molecules can encode mature proteins plusadditional amino or carboxyl-terminal amino acids or both, or aminoacids interior to the mature peptide (when the mature form has more thanone peptide chain, for instance). Such sequences may play a role inprocessing of a protein from precursor to a mature form, facilitateprotein trafficking, prolong or shorten protein half-life, or facilitatemanipulation of a protein for assay or production. As generally is thecase in situ, the additional amino acids may be processed away from themature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limitedto, nucleic acid molecules having a sequence encoding a peptide alone, asequence encoding a mature peptide and additional coding sequences suchas a leader or secretory sequence (e.g., a pre-pro or pro-proteinsequence), a sequence encoding a mature peptide with or withoutadditional coding sequences, plus additional non-coding sequences, forexample introns and non-coding 5′ and 3′ sequences such as transcribedbut untranslated sequences that play a role in, for example,transcription, mRNA processing (including splicing and polyadenylationsignals), ribosome binding, and/or stability of mRNA. In addition, thenucleic acid molecules may be fused to heterologous marker sequencesencoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA,or in the form DNA, including cDNA and genomic DNA, which may beobtained, for example, by molecular cloning or produced by chemicalsynthetic techniques or by a combination thereof (Sambrook and Russell,2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press,NY). Furthermore, isolated nucleic acid molecules, particularly SNPdetection reagents such as probes and primers, can also be partially orcompletely in the form of one or more types of nucleic acid analogs,such as peptide nucleic acid (PNA) (U.S. Pat. Nos. 5,539,082; 5,527,675;5,623,049; 5,714,331). The nucleic acid, especially DNA, can bedouble-stranded or single-stranded. Single-stranded nucleic acid can bethe coding strand (sense strand) or the complementary non-coding strand(anti-sense strand). DNA, RNA, or PNA segments can be assembled, forexample, from fragments of the human genome (in the case of DNA or RNA)or single nucleotides, short oligonucleotide linkers, or from a seriesof oligonucleotides, to provide a synthetic nucleic acid molecule.Nucleic acid molecules can be readily synthesized using the sequencesprovided herein as a reference; oligonucleotide and PNA oligomersynthesis techniques are well known in the art (see, e.g., Corey,“Peptide nucleic acids: expanding the scope of nucleic acidrecognition”, Trends Biotechnol. 1997 June; 15(6):224-9, and Hyrup etal., “Peptide nucleic acids (PNA): synthesis, properties and potentialapplications”, Bioorg Med Chem. 1996 January; 4(1):5-23). Furthermore,large-scale automated oligonucleotide/PNA synthesis (including synthesison an array or bead surface or other solid support) can readily beaccomplished using commercially available nucleic acid synthesizers,such as the Applied Biosystems (Foster City, Calif.) 3900High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid SynthesisSystem, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that containmodified, synthetic, or non-naturally occurring nucleotides orstructural elements or other alternative/modified nucleic acidchemistries known in the art. Such nucleic acid analogs are useful, forexample, as detection reagents (e.g., primers/probes) for detecting oneor more SNPs identified in Table 1 and/or Table 2. Furthermore,kits/systems (such as beads, arrays, etc.) that include these analogsare also encompassed by the present invention. For example, PNAoligomers that are based on the polymorphic sequences of the presentinvention are specifically contemplated. PNA oligomers are analogs ofDNA in which the phosphate backbone is replaced with a peptide-likebackbone (Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters,4: 1081-1082 (1994), Petersen et al., Bioorganic & Medicinal ChemistryLetters, 6: 793-796 (1996), Kumar et al., Organic Letters 3(9):1269-1272 (2001), WO96/04000). PNA hybridizes to complementary RNA orDNA with higher affinity and specificity than conventionaloligonucleotides and oligonucleotide analogs. The properties of PNAenable novel molecular biology and biochemistry applicationsunachievable with traditional oligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve thebinding properties and/or stability of a nucleic acid include the use ofbase analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263)and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, referencesherein to nucleic acid molecules, SNP-containing nucleic acid molecules,SNP detection reagents (e.g., probes and primers),oligonucleotides/polynucleotides include PNA oligomers and other nucleicacid analogs. Other examples of nucleic acid analogs andalternative/modified nucleic acid chemistries known in the art aredescribed in Current Protocols in Nucleic Acid Chemistry, John Wiley &Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules thatencode fragments of the variant polypeptides disclosed herein as well asnucleic acid molecules that encode obvious variants of such variantpolypeptides. Such nucleic acid molecules may be naturally occurring,such as paralogs (different locus) and orthologs (different organism),or may be constructed by recombinant DNA methods or by chemicalsynthesis. Non-naturally occurring variants may be made by mutagenesistechniques, including those applied to nucleic acid molecules, cells, ororganisms. Accordingly, the variants can contain nucleotidesubstitutions, deletions, inversions and insertions (in addition to theSNPs disclosed in Tables 1-2). Variation can occur in either or both thecoding and non-coding regions. The variations can produce conservativeand/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1-2,such as naturally occurring allelic variants (as well as orthologs andparalogs) and synthetic variants produced by mutagenesis techniques, canbe identified and/or produced using methods well known in the art. Suchfurther variants can comprise a nucleotide sequence that shares at least70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity with a nucleic acid sequence disclosed in Table 1and/or Table 2 (or a fragment thereof) and that includes a novel SNPallele disclosed in Table 1 and/or Table 2. Further, variants cancomprise a nucleotide sequence that encodes a polypeptide that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a polypeptide sequence disclosed in Table 1(or a fragment thereof) and that includes a novel SNP allele disclosedin Table 1 and/or Table 2. Thus, an aspect of the present invention thatis specifically contemplated are isolated nucleic acid molecules thathave a certain degree of sequence variation compared with the sequencesshown in Tables 1-2, but that contain a novel SNP allele disclosedherein. In other words, as long as an isolated nucleic acid moleculecontains a novel SNP allele disclosed herein, other portions of thenucleic acid molecule that flank the novel SNP allele can vary to somedegree from the specific transcript, genomic, and context sequencesreferred to and shown in Tables 1-2, and can encode a polypeptide thatvaries to some degree from the specific polypeptide sequences referredto in Table 1.

To determine the percent identity of two amino acid sequences or twonucleotide sequences of two molecules that share sequence homology, thesequences are aligned for optimal comparison purposes (e.g., gaps can beintroduced in one or both of a first and a second amino acid or nucleicacid sequence for optimal alignment and non-homologous sequences can bedisregarded for comparison purposes). In a preferred embodiment, atleast 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of areference sequence is aligned for comparison purposes. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”). Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. (Computational Molecular Biology, Lesk, A. M., ed., OxfordUniversity Press, New York, 1988; Biocomputing: Informatics and GenomeProjects, Smith, D. W., ed., Academic Press, New York, 1993; ComputerAnalysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G.,eds., Humana Press, New Jersey, 1994; Sequence Analysis in MolecularBiology, von Heinje, G., Academic Press, 1987; and Sequence AnalysisPrimer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York,1991). In a preferred embodiment, the percent identity between two aminoacid sequences is determined using the Needleman and Wunsch algorithm(J. Mol. Biol. (48):444-453 (1970)) which has been incorporated into theGAP program in the GCG software package, using either a Blossom 62matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package (Devereux, J., et al., Nucleic Acids Res. 12(1):387(1984)), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60,70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In anotherembodiment, the percent identity between two amino acid or nucleotidesequences is determined using the algorithm of E. Myers and W. Miller(CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention canfurther be used as a “query sequence” to perform a search againstsequence databases to, for example, identify other family members orrelated sequences. Such searches can be performed using the NBLAST andXBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol.215:403-10 (1990)). BLAST nucleotide searches can be performed with theNBLAST program, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to the nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the XBLAST program, score=50,wordlength=3 to obtain amino acid sequences homologous to the proteinsof the invention. To obtain gapped alignments for comparison purposes,Gapped BLAST can be utilized as described in Altschul et al. (NucleicAcids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gappedBLAST programs, the default parameters of the respective programs (e.g.,XBLAST and NBLAST) can be used. In addition to BLAST, examples of othersearch and sequence comparison programs used in the art include, but arenot limited to, FASTA (Pearson, Methods Mol. Biol. 25, 365-389 (1994))and KERR (Dufresne et al., Nat Biotechnol 2002 December;20(12):1269-71). For further information regarding bioinformaticstechniques, see Current Protocols in Bioinformatics, John Wiley & Sons,Inc., N.Y.

The present invention further provides non-coding fragments of thenucleic acid molecules disclosed in Table 1 and/or Table 2. Preferrednon-coding fragments include, but are not limited to, promotersequences, enhancer sequences, intronic sequences, 5′ untranslatedregions (UTRs), 3′ untranslated regions, gene modulating sequences andgene termination sequences. Such fragments are useful, for example, incontrolling heterologous gene expression and in developing screens toidentify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed inTable 1 and/or Table 2, and their associated transcript sequences(referred to in Table 1 as SEQ ID NOS: 1-125), genomic sequences(referred to in Table 2 as SEQ ID NOS: 404-601), and context sequences(transcript-based context sequences are referred to in Table 1 as SEQ IDNOS: 251-403; genomic-based context sequences are provided in Table 2 asSEQ ID NOS: 602-1587), can be used for the design of SNP detectionreagents. The actual sequences referred to in the tables are provided inthe Sequence Listing. As used herein, a “SNP detection reagent” is areagent that specifically detects a specific target SNP positiondisclosed herein, and that is preferably specific for a particularnucleotide (allele) of the target SNP position (i.e., the detectionreagent preferably can differentiate between different alternativenucleotides at a target SNP position, thereby allowing the identity ofthe nucleotide present at the target SNP position to be determined).Typically, such detection reagent hybridizes to a target SNP-containingnucleic acid molecule by complementary base-pairing in a sequencespecific manner, and discriminates the target variant sequence fromother nucleic acid sequences such as an art-known form in a test sample.An example of a detection reagent is a probe that hybridizes to a targetnucleic acid containing one or more of the SNPs referred to in Table 1and/or Table 2. In a preferred embodiment, such a probe candifferentiate between nucleic acids having a particular nucleotide(allele) at a target SNP position from other nucleic acids that have adifferent nucleotide at the same target SNP position. In addition, adetection reagent may hybridize to a specific region 5′ and/or 3′ to aSNP position, particularly a region corresponding to the contextsequences referred to in Table 1 and/or Table 2 (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS: 251-403;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS: 602-1587). Another example of a detection reagent is a primer thatacts as an initiation point of nucleotide extension along acomplementary strand of a target polynucleotide. The SNP sequenceinformation provided herein is also useful for designing primers, e.g.allele-specific primers, to amplify (e.g., using PCR) any SNP of thepresent invention.

In one preferred embodiment of the invention, a SNP detection reagent isan isolated or synthetic DNA or RNA polynucleotide probe or primer orPNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizesto a segment of a target nucleic acid molecule containing a SNPidentified in Table 1 and/or Table 2. A detection reagent in the form ofa polynucleotide may optionally contain modified base analogs,intercalators or minor groove binders. Multiple detection reagents suchas probes may be, for example, affixed to a solid support (e.g., arraysor beads) or supplied in solution (e.g., probe/primer sets for enzymaticreactions such as PCR, RT-PCR, TaqMan assays, or primer-extensionreactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotideor PNA oligomer. Such oligonucleotide typically comprises a region ofcomplementary nucleotide sequence that hybridizes under stringentconditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50,55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) ormore consecutive nucleotides in a target nucleic acid molecule.Depending on the particular assay, the consecutive nucleotides caneither include the target SNP position, or be a specific region in closeenough proximity 5′ and/or 3′ to the SNP position to carry out thedesired assay.

Other preferred primer and probe sequences can readily be determinedusing the transcript sequences (SEQ ID NOS: 1-125), genomic sequences(SEQ ID NOS: 404-601), and SNP context sequences (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS: 251-403;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS: 602-1587) disclosed in the Sequence Listing and in Tables 1-2. Theactual sequences referred to in the tables are provided in the SequenceListing. It will be apparent to one of skill in the art that suchprimers and probes are directly useful as reagents for genotyping theSNPs of the present invention, and can be incorporated into anykit/system format.

In order to produce a probe or primer specific for a targetSNP-containing sequence, the gene/transcript and/or context sequencesurrounding the SNP of interest is typically examined using a computeralgorithm that starts at the 5′ or at the 3′ end of the nucleotidesequence. Typical algorithms will then identify oligomers of definedlength that are unique to the gene/SNP context sequence, have a GCcontent within a range suitable for hybridization, lack predictedsecondary structure that may interfere with hybridization, and/orpossess other desired characteristics or that lack other undesiredcharacteristics.

A primer or probe of the present invention is typically at least about 8nucleotides in length. In one embodiment of the invention, a primer or aprobe is at least about 10 nucleotides in length. In a preferredembodiment, a primer or a probe is at least about 12 nucleotides inlength. In a more preferred embodiment, a primer or probe is at leastabout 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length.While the maximal length of a probe can be as long as the targetsequence to be detected, depending on the type of assay in which it isemployed, it is typically less than about 50, 60, 65, or 70 nucleotidesin length. In the case of a primer, it is typically less than about 30nucleotides in length. In a specific preferred embodiment of theinvention, a primer or a probe is within the length of about 18 andabout 28 nucleotides. However, in other embodiments, such as nucleicacid arrays and other embodiments in which probes are affixed to asubstrate, the probes can be longer, such as on the order of 30-70, 75,80, 90, 100, or more nucleotides in length (see the section belowentitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotidesspecific for alternative SNP alleles. Such oligonucleotides that detectsingle nucleotide variations in target sequences may be referred to bysuch terms as “allele-specific oligonucleotides”, “allele-specificprobes”, or “allele-specific primers”. The design and use ofallele-specific probes for analyzing polymorphisms is described in,e.g., Mutation Detection A Practical Approach, ed. Cotton et al. OxfordUniversity Press, 1998; Saiki et al., Nature 324, 163-166 (1986);Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends onvariables such as the precise composition of the nucleotide sequencesflanking a SNP position in a target nucleic acid molecule, and thelength of the primer or probe, another factor in the use of primers andprobes is the stringency of the condition under which the hybridizationbetween the probe or primer and the target sequence is performed. Higherstringency conditions utilize buffers with lower ionic strength and/or ahigher reaction temperature, and tend to require a more perfect matchbetween probe/primer and a target sequence in order to form a stableduplex. If the stringency is too high, however, hybridization may notoccur at all. In contrast, lower stringency conditions utilize bufferswith higher ionic strength and/or a lower reaction temperature, andpermit the formation of stable duplexes with more mismatched basesbetween a probe/primer and a target sequence. By way of example and notlimitation, exemplary conditions for high stringency hybridizationconditions using an allele-specific probe are as follows:prehybridization with a solution containing 5× standard saline phosphateEDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe withtarget nucleic acid molecules in the same solution at the sametemperature, followed by washing with a solution containing 2×SSPE, and0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used forallele-specific primer extension reactions with a solution containing,e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may becarried out at an elevated temperature such as 60° C. In anotherembodiment, a moderately stringent hybridization condition suitable foroligonucleotide ligation assay (OLA) reactions wherein two probes areligated if they are completely complementary to the target sequence mayutilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designedthat hybridize to a segment of target DNA from one individual but do nothybridize to the corresponding segment from another individual due tothe presence of different polymorphic forms (e.g., alternative SNPalleles/nucleotides) in the respective DNA segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant detectable difference in hybridizationintensity between alleles, and preferably an essentially binaryresponse, whereby a probe hybridizes to only one of the alleles orsignificantly more strongly to one allele. While a probe may be designedto hybridize to a target sequence that contains a SNP site such that theSNP site aligns anywhere along the sequence of the probe, the probe ispreferably designed to hybridize to a segment of the target sequencesuch that the SNP site aligns with a central position of the probe(e.g., a position within the probe that is at least three nucleotidesfrom either end of the probe). This design of probe generally achievesgood discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize toa segment of target DNA such that the SNP aligns with either the 5′ mostend or the 3′ most end of the probe or primer. In a specific preferredembodiment that is particularly suitable for use in a oligonucleotideligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of theprobe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well knownin the art. Chemical synthetic methods include, but are limited to, thephosphotriester method described by Narang et al., 1979, Methods inEnzymology 68:90; the phosphodiester method described by Brown et al.,1979, Methods in Enzymology 68:109, the diethylphosphoamidate methoddescribed by Beaucage et al., 1981, Tetrahedron Letters 22:1859; and thesolid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, insets of 3 or 4, such as if a SNP position is known to have 3 or 4alleles, respectively, or to assay both strands of a nucleic acidmolecule for a target SNP allele), and such pairs may be identicalexcept for a one nucleotide mismatch that represents the allelicvariants at the SNP position. Commonly, one member of a pair perfectlymatches a reference form of a target sequence that has a more common SNPallele (i.e., the allele that is more frequent in the target population)and the other member of the pair perfectly matches a form of the targetsequence that has a less common SNP allele (i.e., the allele that israrer in the target population). In the case of an array, multiple pairsof probes can be immobilized on the same support for simultaneousanalysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes toa region on a target nucleic acid molecule that overlaps a SNP positionand only primes amplification of an allelic form to which the primerexhibits perfect complementarity (Gibbs, 1989, Nucleic Acid Res. 172427-2448). Typically, the primer's 3′-most nucleotide is aligned withand complementary to the SNP position of the target nucleic acidmolecule. This primer is used in conjunction with a second primer thathybridizes at a distal site. Amplification proceeds from the twoprimers, producing a detectable product that indicates which allelicform is present in the test sample. A control is usually performed witha second pair of primers, one of which shows a single base mismatch atthe polymorphic site and the other of which exhibits perfectcomplementarity to a distal site. The single-base mismatch preventsamplification or substantially reduces amplification efficiency, so thateither no detectable product is formed or it is formed in lower amountsor at a slower pace. The method generally works most effectively whenthe mismatch is at the 3′-most position of the oligonucleotide (i.e.,the 3′-most position of the oligonucleotide aligns with the target SNPposition) because this position is most destabilizing to elongation fromthe primer (see, e.g., WO 93/22456). This PCR-based assay can beutilized as part of the TaqMan assay, described below.

In a specific embodiment of the invention, a primer of the inventioncontains a sequence substantially complementary to a segment of a targetSNP-containing nucleic acid molecule except that the primer has amismatched nucleotide in one of the three nucleotide positions at the3′-most end of the primer, such that the mismatched nucleotide does notbase pair with a particular allele at the SNP site. In a preferredembodiment, the mismatched nucleotide in the primer is the second fromthe last nucleotide at the 3′-most position of the primer. In a morepreferred embodiment, the mismatched nucleotide in the primer is thelast nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of theinvention is labeled with a fluorogenic reporter dye that emits adetectable signal. While the preferred reporter dye is a fluorescentdye, any reporter dye that can be attached to a detection reagent suchas an oligonucleotide probe or primer is suitable for use in theinvention. Such dyes include, but are not limited to, Acridine, AMCA,BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin,Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine,Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may befurther labeled with a quencher dye such as Tamra, especially when thereagent is used as a self-quenching probe such as a TaqMan (U.S. Pat.Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos.5,118,801 and 5,312,728), or other stemless or linear beacon probe(Livak et al., 1995, PCR Method Appl. 4:357-362; Tyagi et al., 1996,Nature Biotechnology 14: 303-308; Nazarenko et al., 1997, Nucl. AcidsRes. 25:2516-2521; U.S. Pat. Nos. 5,866,336 and 6,117,635).

The detection reagents of the invention may also contain other labels,including but not limited to, biotin for streptavidin binding, haptenfor antibody binding, and oligonucleotide for binding to anothercomplementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (orthat are complementary to) a SNP nucleotide identified herein but thatare used to assay one or more SNPs disclosed herein. For example,primers that flank, but do not hybridize directly to a target SNPposition provided herein are useful in primer extension reactions inwhich the primers hybridize to a region adjacent to the target SNPposition (i.e., within one or more nucleotides from the target SNPsite). During the primer extension reaction, a primer is typically notable to extend past a target SNP site if a particular nucleotide(allele) is present at that target SNP site, and the primer extensionproduct can be detected in order to determine which SNP allele ispresent at the target SNP site. For example, particular ddNTPs aretypically used in the primer extension reaction to terminate primerextension once a ddNTP is incorporated into the extension product (aprimer extension product which includes a ddNTP at the 3′-most end ofthe primer extension product, and in which the ddNTP is a nucleotide ofa SNP disclosed herein, is a composition that is specificallycontemplated by the present invention). Thus, reagents that bind to anucleic acid molecule in a region adjacent to a SNP site and that areused for assaying the SNP site, even though the bound sequences do notnecessarily include the SNP site itself, are also contemplated by thepresent invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP andassociated sequence information disclosed herein, detection reagents canbe developed and used to assay any SNP of the present inventionindividually or in combination, and such detection reagents can bereadily incorporated into one of the established kit or system formatswhich are well known in the art. The terms “kits” and “systems”, as usedherein in the context of SNP detection reagents, are intended to referto such things as combinations of multiple SNP detection reagents, orone or more SNP detection reagents in combination with one or more othertypes of elements or components (e.g., other types of biochemicalreagents, containers, packages such as packaging intended for commercialsale, substrates to which SNP detection reagents are attached,electronic hardware components, etc.). Accordingly, the presentinvention further provides SNP detection kits and systems, including butnot limited to, packaged probe and primer sets (e.g., TaqManprobe/primer sets), arrays/microarrays of nucleic acid molecules, andbeads that contain one or more probes, primers, or other detectionreagents for detecting one or more SNPs of the present invention. Thekits/systems can optionally include various electronic hardwarecomponents; for example, arrays (“DNA chips”) and microfluidic systems(“lab-on-a-chip” systems) provided by various manufacturers typicallycomprise hardware components. Other kits/systems (e.g., probe/primersets) may not include electronic hardware components, but may becomprised of, for example, one or more SNP detection reagents (alongwith, optionally, other biochemical reagents) packaged in one or morecontainers.

In some embodiments, a SNP detection kit typically contains one or moredetection reagents and other components (e.g., a buffer, enzymes such asDNA polymerases or ligases, chain extension nucleotides such asdeoxynucleotide triphosphates, and in the case of Sanger-type DNAsequencing reactions, chain terminating nucleotides, positive controlsequences, negative control sequences, and the like) necessary to carryout an assay or reaction, such as amplification and/or detection of aSNP-containing nucleic acid molecule. A kit may further contain meansfor determining the amount of a target nucleic acid, and means forcomparing the amount with a standard, and can comprise instructions forusing the kit to detect the SNP-containing nucleic acid molecule ofinterest. In one embodiment of the present invention, kits are providedwhich contain the necessary reagents to carry out one or more assays todetect one or more SNPs disclosed herein. In a preferred embodiment ofthe present invention, SNP detection kits/systems are in the form ofnucleic acid arrays, or compartmentalized kits, includingmicrofluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes,or pairs of probes, that hybridize to a nucleic acid molecule at or neareach target SNP position. Multiple pairs of allele-specific probes maybe included in the kit/system to simultaneously assay large numbers ofSNPs, at least one of which is a SNP of the present invention. In somekits/systems, the allele-specific probes are immobilized to a substratesuch as an array or bead. For example, the same substrate can compriseallele-specific probes for detecting at least 1; 10; 100; 1000; 10,000;100,000 (or any other number in-between) or substantially all of theSNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used hereininterchangeably to refer to an array of distinct polynucleotides affixedto a substrate, such as glass, plastic, paper, nylon or other type ofmembrane, filter, chip, or any other suitable solid support. Thepolynucleotides can be synthesized directly on the substrate, orsynthesized separate from the substrate and then affixed to thesubstrate. In one embodiment, the microarray is prepared and usedaccording to the methods described in U.S. Pat. No. 5,837,832, Chee etal., PCT application W095/11995 (Chee et al.), Lockhart, D. J. et al.(1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc.Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated hereinin their entirety by reference. In other embodiments, such arrays areproduced by the methods described by Brown et al., U.S. Pat. No.5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteoet al., “New chips for molecular biology and diagnostics”, BiotechnolAnnu Rev. 2002; 8:85-101; Sosnowski et al., “Active microelectronicarray system for DNA hybridization, genotyping and pharmacogenomicapplications”, Psychiatr Genet. 2002 December; 12(4): 181-92; Heller,“DNA microarray technology: devices, systems, and applications”, AnnuRev Biomed Eng. 2002; 4:129-53. Epub 2002 Mar. 22; Kolchinsky et al.,“Analysis of SNPs and other genomic variations using gel-based chips”,Hum Mutat. 2002 April; 19(4):343-60; and McGall et al., “High-densitygenechip oligonucleotide probe arrays”, Adv Biochem Eng Biotechnol.2002; 77:21-42.

Any number of probes, such as allele-specific probes, may be implementedin an array, and each probe or pair of probes can hybridize to adifferent SNP position. In the case of polynucleotide probes, they canbe synthesized at designated areas (or synthesized separately and thenaffixed to designated areas) on a substrate using a light-directedchemical process. Each DNA chip can contain, for example, thousands tomillions of individual synthetic polynucleotide probes arranged in agrid-like pattern and miniaturized (e.g., to the size of a dime).Preferably, probes are attached to a solid support in an ordered,addressable array.

A microarray can be composed of a large number of unique,single-stranded polynucleotides, usually either synthetic antisensepolynucleotides or fragments of cDNAs, fixed to a solid support. Typicalpolynucleotides are preferably about 6-60 nucleotides in length, morepreferably about 15-30 nucleotides in length, and most preferably about18-25 nucleotides in length. For certain types of microarrays or otherdetection kits/systems, it may be preferable to use oligonucleotidesthat are only about 7-20 nucleotides in length. In other types ofarrays, such as arrays used in conjunction with chemiluminescentdetection technology, preferred probe lengths can be, for example, about15-80 nucleotides in length, preferably about 50-70 nucleotides inlength, more preferably about 55-65 nucleotides in length, and mostpreferably about 60 nucleotides in length. The microarray or detectionkit can contain polynucleotides that cover the known 5′ or 3′ sequenceof a gene/transcript or target SNP site, sequential polynucleotides thatcover the full-length sequence of a gene/transcript; or uniquepolynucleotides selected from particular areas along the length of atarget gene/transcript sequence, particularly areas corresponding to oneor more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides usedin the microarray or detection kit can be specific to a SNP or SNPs ofinterest (e.g., specific to a particular SNP allele at a target SNPsite, or specific to particular SNP alleles at multiple different SNPsites), or specific to a polymorphic gene/transcript orgenes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on thedifferences in hybridization stability of the probes to perfectlymatched and mismatched target sequence variants. For SNP genotyping, itis generally preferable that stringency conditions used in hybridizationassays are high enough such that nucleic acid molecules that differ fromone another at as little as a single SNP position can be differentiated(e.g., typical SNP hybridization assays are designed so thathybridization will occur only if one particular nucleotide is present ata SNP position, but will not occur if an alternative nucleotide ispresent at that SNP position). Such high stringency conditions may bepreferable when using, for example, nucleic acid arrays ofallele-specific probes for SNP detection. Such high stringencyconditions are described in the preceding section, and are well known tothose skilled in the art and can be found in, for example, CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y. (1989),6.3.1-6.3.6.

In other embodiments, the arrays are used in conjunction withchemiluminescent detection technology. The following patents and patentapplications, which are all hereby incorporated by reference, provideadditional information pertaining to chemiluminescent detection: U.S.patent application Ser. Nos. 10/620,332 and 10/620,333 describechemiluminescent approaches for microarray detection; U.S. Pat. Nos.6,124,478, 6,107,024, 5,994,073, 5,981,768, 5,871,938, 5,843,681,5,800,999, and 5,773,628 describe methods and compositions of dioxetanefor performing chemiluminescent detection; and U.S. publishedapplication US2002/0110828 discloses methods and compositions formicroarray controls.

In one embodiment of the invention, a nucleic acid array can comprise anarray of probes of about 15-25 nucleotides in length. In furtherembodiments, a nucleic acid array can comprise any number of probes, inwhich at least one probe is capable of detecting one or more SNPsdisclosed in Table 1 and/or Table 2, and/or at least one probe comprisesa fragment of one of the sequences selected from the group consisting ofthose disclosed in Table 1, Table 2, the Sequence Listing, and sequencescomplementary thereto, said fragment comprising at least about 8consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, morepreferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or moreconsecutive nucleotides (or any other number in-between) and containing(or being complementary to) a novel SNP allele disclosed in Table 1and/or Table 2. In some embodiments, the nucleotide complementary to theSNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of theprobe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of thesubstrate by using a chemical coupling procedure and an ink jetapplication apparatus, as described in PCT application W095/251116(Baldeschweiler et al.) which is incorporated herein in its entirety byreference. In another aspect, a “gridded” array analogous to a dot (orslot) blot may be used to arrange and link cDNA fragments oroligonucleotides to the surface of a substrate using a vacuum system,thermal, UV, mechanical or chemical bonding procedures. An array, suchas those described above, may be produced by hand or by using availabledevices (slot blot or dot blot apparatus), materials (any suitable solidsupport), and machines (including robotic instruments), and may contain8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other numberwhich lends itself to the efficient use of commercially availableinstrumentation.

Using such arrays or other kits/systems, the present invention providesmethods of identifying the SNPs disclosed herein in a test sample. Suchmethods typically involve incubating a test sample of nucleic acids withan array comprising one or more probes corresponding to at least one SNPposition of the present invention, and assaying for binding of a nucleicacid from the test sample with one or more of the probes. Conditions forincubating a SNP detection reagent (or a kit/system that employs one ormore such SNP detection reagents) with a test sample vary. Incubationconditions depend on such factors as the format employed in the assay,the detection methods employed, and the type and nature of the detectionreagents used in the assay. One skilled in the art will recognize thatany one of the commonly available hybridization, amplification and arrayassay formats can readily be adapted to detect the SNPs disclosedherein.

A SNP detection kit/system of the present invention may includecomponents that are used to prepare nucleic acids from a test sample forthe subsequent amplification and/or detection of a SNP-containingnucleic acid molecule. Such sample preparation components can be used toproduce nucleic acid extracts (including DNA and/or RNA), proteins ormembrane extracts from any bodily fluids (such as blood, serum, plasma,urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin,hair, cells (especially nucleated cells), biopsies, buccal swabs ortissue specimens. The test samples used in the above-described methodswill vary based on such factors as the assay format, nature of thedetection method, and the specific tissues, cells or extracts used asthe test sample to be assayed. Methods of preparing nucleic acids,proteins, and cell extracts are well known in the art and can be readilyadapted to obtain a sample that is compatible with the system utilized.Automated sample preparation systems for extracting nucleic acids from atest sample are commercially available, and examples are Qiagen'sBioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparationsystem, and Roche Molecular Systems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is acompartmentalized kit. A compartmentalized kit includes any kit in whichreagents are contained in separate containers. Such containers include,for example, small glass containers, plastic containers, strips ofplastic, glass or paper, or arraying material such as silica. Suchcontainers allow one to efficiently transfer reagents from onecompartment to another compartment such that the test samples andreagents are not cross-contaminated, or from one container to anothervessel not included in the kit, and the agents or solutions of eachcontainer can be added in a quantitative fashion from one compartment toanother or to another vessel. Such containers may include, for example,one or more containers which will accept the test sample, one or morecontainers which contain at least one probe or other SNP detectionreagent for detecting one or more SNPs of the present invention, one ormore containers which contain wash reagents (such as phosphate bufferedsaline, Tris-buffers, etc.), and one or more containers which containthe reagents used to reveal the presence of the bound probe or other SNPdetection reagents. The kit can optionally further comprise compartmentsand/or reagents for, for example, nucleic acid amplification or otherenzymatic reactions such as primer extension reactions, hybridization,ligation, electrophoresis (preferably capillary electrophoresis), massspectrometry, and/or laser-induced fluorescent detection. The kit mayalso include instructions for using the kit. Exemplary compartmentalizedkits include microfluidic devices known in the art (see, e.g., Weigl etal., “Lab-on-a-chip for drug development”, Adv Drug Deliv Rev. 2003 Feb.24; 55(3):349-77). In such microfluidic devices, the containers may bereferred to as, for example, microfluidic “compartments”, “chambers”, or“channels”.

Microfluidic devices, which may also be referred to as “lab-on-a-chip”systems, biomedical micro-electro-mechanical systems (bioMEMs), ormulticomponent integrated systems, are exemplary kits/systems of thepresent invention for analyzing SNPs. Such systems miniaturize andcompartmentalize processes such as probe/target hybridization, nucleicacid amplification, and capillary electrophoresis reactions in a singlefunctional device. Such microfluidic devices typically utilize detectionreagents in at least one aspect of the system, and such detectionreagents may be used to detect one or more SNPs of the presentinvention. One example of a microfluidic system is disclosed in U.S.Pat. No. 5,589,136, which describes the integration of PCR amplificationand capillary electrophoresis in chips. Exemplary microfluidic systemscomprise a pattern of microchannels designed onto a glass, silicon,quartz, or plastic wafer included on a microchip. The movements of thesamples may be controlled by electric, electroosmotic or hydrostaticforces applied across different areas of the microchip to createfunctional microscopic valves and pumps with no moving parts. Varyingthe voltage can be used as a means to control the liquid flow atintersections between the micro-machined channels and to change theliquid flow rate for pumping across different sections of the microchip.See, for example, U.S. Pat. Nos. 6,153,073, Dubrow et al., and6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, forexample, nucleic acid amplification, primer extension, capillaryelectrophoresis, and a detection method such as laser inducedfluorescence detection. In a first step of an exemplary process forusing such an exemplary system, nucleic acid samples are amplified,preferably by PCR. Then, the amplification products are subjected toautomated primer extension reactions using ddNTPs (specific fluorescencefor each ddNTP) and the appropriate oligonucleotide primers to carry outprimer extension reactions which hybridize just upstream of the targetedSNP. Once the extension at the 3′ end is completed, the primers areseparated from the unincorporated fluorescent ddNTPs by capillaryelectrophoresis. The separation medium used in capillary electrophoresiscan be, for example, polyacrylamide, polyethyleneglycol or dextran. Theincorporated ddNTPs in the single nucleotide primer extension productsare identified by laser-induced fluorescence detection. Such anexemplary microchip can be used to process, for example, at least 96 to384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety ofuses, especially in the diagnosis and treatment of VT. For example, thenucleic acid molecules are useful as hybridization probes, such as forgenotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA,amplified DNA or other nucleic acid molecules, and for isolatingfull-length cDNA and genomic clones encoding the variant peptidesdisclosed in Table 1 as well as their orthologs.

A probe can hybridize to any nucleotide sequence along the entire lengthof a nucleic acid molecule referred to in Table 1 and/or Table 2.Preferably, a probe of the present invention hybridizes to a region of atarget sequence that encompasses a SNP position indicated in Table 1and/or Table 2. More preferably, a probe hybridizes to a SNP-containingtarget sequence in a sequence-specific manner such that it distinguishesthe target sequence from other nucleotide sequences which vary from thetarget sequence only by which nucleotide is present at the SNP site.Such a probe is particularly useful for detecting the presence of aSNP-containing nucleic acid in a test sample, or for determining whichnucleotide (allele) is present at a particular SNP site (i.e.,genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining thepresence, level, form, and/or distribution of nucleic acid expression.The nucleic acid whose level is determined can be DNA or RNA.Accordingly, probes specific for the SNPs described herein can be usedto assess the presence, expression and/or gene copy number in a givencell, tissue, or organism. These uses are relevant for diagnosis ofdisorders involving an increase or decrease in gene expression relativeto normal levels. In vitro techniques for detection of mRNA include, forexample, Northern blot hybridizations and in situ hybridizations. Invitro techniques for detecting DNA include Southern blot hybridizationsand in situ hybridizations (Sambrook and Russell, 2000, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Press, Cold SpringHarbor, N.Y.).

Probes can be used as part of a diagnostic test kit for identifyingcells or tissues in which a variant protein is expressed, such as bymeasuring the level of a variant protein-encoding nucleic acid (e.g.,mRNA) in a sample of cells from a subject or determining if apolynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used ashybridization probes to detect the SNPs disclosed herein, therebydetermining whether an individual with the polymorphisms is at risk forVT or has developed early stage VT. Detection of a SNP associated with adisease phenotype provides a diagnostic tool for an active diseaseand/or genetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are thereforeuseful for detecting a gene (gene information is disclosed in Table 2,for example) which contains a SNP disclosed herein and/or products ofsuch genes, such as expressed mRNA transcript molecules (transcriptinformation is disclosed in Table 1, for example), and are thus usefulfor detecting gene expression. The nucleic acid molecules can optionallybe implemented in, for example, an array or kit format for use indetecting gene expression.

The nucleic acid molecules of the invention are also useful as primersto amplify any given region of a nucleic acid molecule, particularly aregion containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful forconstructing recombinant vectors (described in greater detail below).Such vectors include expression vectors that express a portion of, orall of, any of the variant peptide sequences referred to in Table 1.Vectors also include insertion vectors, used to integrate into anothernucleic acid molecule sequence, such as into the cellular genome, toalter in situ expression of a gene and/or gene product. For example, anendogenous coding sequence can be replaced via homologous recombinationwith all or part of the coding region containing one or morespecifically introduced SNPs.

The nucleic acid molecules of the invention are also useful forexpressing antigenic portions of the variant proteins, particularlyantigenic portions that contain a variant amino acid sequence (e.g., anamino acid substitution) caused by a SNP disclosed in Table 1 and/orTable 2.

The nucleic acid molecules of the invention are also useful forconstructing vectors containing a gene regulatory region of the nucleicacid molecules of the present invention.

The nucleic acid molecules of the invention are also useful fordesigning ribozymes corresponding to all, or a part, of an mRNA moleculeexpressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful forconstructing host cells expressing a part, or all, of the nucleic acidmolecules and variant peptides.

The nucleic acid molecules of the invention are also useful forconstructing transgenic animals expressing all, or a part, of thenucleic acid molecules and variant peptides. The production ofrecombinant cells and transgenic animals having nucleic acid moleculeswhich contain the SNPs disclosed in Table 1 and/or Table 2 allow, forexample, effective clinical design of treatment compounds and dosageregimens.

The nucleic acid molecules of the invention are also useful in assaysfor drug screening to identify compounds that, for example, modulatenucleic acid expression.

The nucleic acid molecules of the invention are also useful in genetherapy in patients whose cells have aberrant gene expression. Thus,recombinant cells, which include a patient's cells that have beenengineered ex vivo and returned to the patient, can be introduced intoan individual where the recombinant cells produce the desired protein totreat the individual.

SNP Genotyping Methods

The process of determining which specific nucleotide (i.e., allele) ispresent at each of one or more SNP positions, such as a SNP position ina nucleic acid molecule disclosed in Table 1 and/or Table 2, is referredto as SNP genotyping. The present invention provides methods of SNPgenotyping, such as for use in screening for VT or related pathologies,or determining predisposition thereto, or determining responsiveness toa form of treatment, or in genome mapping or SNP association analysis,etc.

Nucleic acid samples can be genotyped to determine which allele(s)is/are present at any given genetic region (e.g., SNP position) ofinterest by methods well known in the art. The neighboring sequence canbe used to design SNP detection reagents such as oligonucleotide probes,which may optionally be implemented in a kit format. Exemplary SNPgenotyping methods are described in Chen et al., “Single nucleotidepolymorphism genotyping: biochemistry, protocol, cost and throughput”,Pharmacogenomics J. 2003; 3(2):77-96; Kwok et al., “Detection of singlenucleotide polymorphisms”, Curr Issues Mol Biol. 2003 April; 5(2):43-60;Shi, “Technologies for individual genotyping: detection of geneticpolymorphisms in drug targets and disease genes”, Am J Pharmacogenomics.2002; 2(3): 197-205; and Kwok, “Methods for genotyping single nucleotidepolymorphisms”, Annu Rev Genomics Hum Genet 2001; 2:235-58. Exemplarytechniques for high-throughput SNP genotyping are described inMarnellos, “High-throughput SNP analysis for genetic associationstudies”, Curr Opin Drug Discov Devel. 2003 May; 6(3):317-21. Common SNPgenotyping methods include, but are not limited to, TaqMan assays,molecular beacon assays, nucleic acid arrays, allele-specific primerextension, allele-specific PCR, arrayed primer extension, homogeneousprimer extension assays, primer extension with detection by massspectrometry, pyrosequencing, multiplex primer extension sorted ongenetic arrays, ligation with rolling circle amplification, homogeneousligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reactionsorted on genetic arrays, restriction-fragment length polymorphism,single base extension-tag assays, and the Invader assay. Such methodsmay be used in combination with detection mechanisms such as, forexample, luminescence or chemiluminescence detection, fluorescencedetection, time-resolved fluorescence detection, fluorescence resonanceenergy transfer, fluorescence polarization, mass spectrometry, andelectrical detection.

Various methods for detecting polymorphisms include, but are not limitedto, methods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al,Meth. Enzymol. 217:286-295 (1992)), comparison of the electrophoreticmobility of variant and wild type nucleic acid molecules (Orita et al.,PNAS 86:2766 (1989); Cotton et al., Mutat. Res. 285:125-144 (1993); andHayashi et al., Genet. Anal Tech. Appl. 9:73-79 (1992)), and assayingthe movement of polymorphic or wild-type fragments in polyacrylamidegels containing a gradient of denaturant using denaturing gradient gelelectrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequencevariations at specific locations can also be assessed by nucleaseprotection assays such as RNase and S1 protection or chemical cleavagemethods.

In a preferred embodiment, SNP genotyping is performed using the TaqManassay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos.5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of aspecific amplified product during PCR. The TaqMan assay utilizes anoligonucleotide probe labeled with a fluorescent reporter dye and aquencher dye. The reporter dye is excited by irradiation at anappropriate wavelength, it transfers energy to the quencher dye in thesame probe via a process called fluorescence resonance energy transfer(FRET). When attached to the probe, the excited reporter dye does notemit a signal. The proximity of the quencher dye to the reporter dye inthe intact probe maintains a reduced fluorescence for the reporter. Thereporter dye and quencher dye may be at the 5′ most and the 3′ mostends, respectively, or vice versa. Alternatively, the reporter dye maybe at the 5′ or 3′ most end while the quencher dye is attached to aninternal nucleotide, or vice versa. In yet another embodiment, both thereporter and the quencher may be attached to internal nucleotides at adistance from each other such that fluorescence of the reporter isreduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves theprobe, thereby separating the reporter dye and the quencher dye andresulting in increased fluorescence of the reporter. Accumulation of PCRproduct is detected directly by monitoring the increase in fluorescenceof the reporter dye. The DNA polymerase cleaves the probe between thereporter dye and the quencher dye only if the probe hybridizes to thetarget SNP-containing template which is amplified during PCR, and theprobe is designed to hybridize to the target SNP site only if aparticular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determinedusing the SNP and associated nucleic acid sequence information providedherein. A number of computer programs, such as Primer Express (AppliedBiosystems, Foster City, Calif.), can be used to rapidly obtain optimalprimer/probe sets. It will be apparent to one of skill in the art thatsuch primers and probes for detecting the SNPs of the present inventionare useful in diagnostic assays for VT and related pathologies, and canbe readily incorporated into a kit format. The present invention alsoincludes modifications of the Taqman assay well known in the art such asthe use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and6,117,635).

Another preferred method for genotyping the SNPs of the presentinvention is the use of two oligonucleotide probes in an OLA (see, e.g.,U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to asegment of a target nucleic acid with its 3′ most end aligned with theSNP site. A second probe hybridizes to an adjacent segment of the targetnucleic acid molecule directly 3′ to the first probe. The two juxtaposedprobes hybridize to the target nucleic acid molecule, and are ligated inthe presence of a linking agent such as a ligase if there is perfectcomplementarity between the 3′ most nucleotide of the first probe withthe SNP site. If there is a mismatch, ligation would not occur. Afterthe reaction, the ligated probes are separated from the target nucleicacid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published internationalpatent applications, which are all hereby incorporated by reference,provide additional information pertaining to techniques for carrying outvarious types of OLA: U.S. Pat. Nos. 6,027,889, 6,268,148, 5,494,810,5,830,711, and 6,054,564 describe OLA strategies for performing SNPdetection; WO 97/31256 and WO 00/56927 describe OLA strategies forperforming SNP detection using universal arrays, wherein a zipcodesequence can be introduced into one of the hybridization probes, and theresulting product, or amplified product, hybridized to a universal zipcode array; U.S. application Ser. No. 01/17329 (and Ser. No. 09/584,905)describes OLA (or LDR) followed by PCR, wherein zipcodes areincorporated into OLA probes, and amplified PCR products are determinedby electrophoretic or universal zipcode array readout; U.S. applications60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods andsoftware for multiplexed SNP detection using OLA followed by PCR,wherein zipcodes are incorporated into OLA probes, and amplified PCRproducts are hybridized with a zipchute reagent, and the identity of theSNP determined from electrophoretic readout of the zipchute. In someembodiments, OLA is carried out prior to PCR (or another method ofnucleic acid amplification). In other embodiments, PCR (or anothermethod of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Massspectrometry takes advantage of the unique mass of each of the fournucleotides of DNA. SNPs can be unambiguously genotyped by massspectrometry by measuring the differences in the mass of nucleic acidshaving alternative SNP alleles. MALDI-TOF (Matrix Assisted LaserDesorption Ionization—Time of Flight) mass spectrometry technology ispreferred for extremely precise determinations of molecular mass, suchas SNPs. Numerous approaches to SNP analysis have been developed basedon mass spectrometry. Preferred mass spectrometry-based methods of SNPgenotyping include primer extension assays, which can also be utilizedin combination with other approaches, such as traditional gel-basedformats and microarrays.

Typically, the primer extension assay involves designing and annealing aprimer to a template PCR amplicon upstream (5′) from a target SNPposition. A mix of dideoxynucleotide triphosphates (ddNTPs) and/ordeoxynucleotide triphosphates (dNTPs) are added to a reaction mixturecontaining template (e.g., a SNP-containing nucleic acid molecule whichhas typically been amplified, such as by PCR), primer, and DNApolymerase. Extension of the primer terminates at the first position inthe template where a nucleotide complementary to one of the ddNTPs inthe mix occurs. The primer can be either immediately adjacent (i.e., thenucleotide at the 3′ end of the primer hybridizes to the nucleotide nextto the target SNP site) or two or more nucleotides removed from the SNPposition. If the primer is several nucleotides removed from the targetSNP position, the only limitation is that the template sequence betweenthe 3′ end of the primer and the SNP position cannot contain anucleotide of the same type as the one to be detected, or this willcause premature termination of the extension primer. Alternatively, ifall four ddNTPs alone, with no dNTPs, are added to the reaction mixture,the primer will always be extended by only one nucleotide, correspondingto the target SNP position. In this instance, primers are designed tobind one nucleotide upstream from the SNP position (i.e., the nucleotideat the 3′ end of the primer hybridizes to the nucleotide that isimmediately adjacent to the target SNP site on the 5′ side of the targetSNP site). Extension by only one nucleotide is preferable, as itminimizes the overall mass of the extended primer, thereby increasingthe resolution of mass differences between alternative SNP nucleotides.Furthermore, mass-tagged ddNTPs can be employed in the primer extensionreactions in place of unmodified ddNTPs. This increases the massdifference between primers extended with these ddNTPs, thereby providingincreased sensitivity and accuracy, and is particularly useful fortyping heterozygous base positions. Mass-tagging also alleviates theneed for intensive sample-preparation procedures and decreases thenecessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF massspectrometry to determine the identity of the nucleotide present at thetarget SNP position. In one method of analysis, the products from theprimer extension reaction are combined with light absorbing crystalsthat form a matrix. The matrix is then hit with an energy source such asa laser to ionize and desorb the nucleic acid molecules into thegas-phase. The ionized molecules are then ejected into a flight tube andaccelerated down the tube towards a detector. The time between theionization event, such as a laser pulse, and collision of the moleculewith the detector is the time of flight of that molecule. The time offlight is precisely correlated with the mass-to-charge ratio (m/z) ofthe ionized molecule. Ions with smaller m/z travel down the tube fasterthan ions with larger m/z and therefore the lighter ions reach thedetector before the heavier ions. The time-of-flight is then convertedinto a corresponding, and highly precise, m/z. In this manner, SNPs canbe identified based on the slight differences in mass, and thecorresponding time of flight differences, inherent in nucleic acidmolecules having different nucleotides at a single base position. Forfurther information regarding the use of primer extension assays inconjunction with MALDI-TOF mass spectrometry for SNP genotyping, see,e.g., Wise et al., “A standard protocol for single nucleotide primerextension in the human genome using matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry”, Rapid CommunMass Spectrom. 2003; 17(11): 1195-202.

The following references provide further information describing massspectrometry-based methods for SNP genotyping: Bocker, “SNP and mutationdiscovery using base-specific cleavage and MALDI-TOF mass spectrometry”,Bioinformatics. 2003 July; 19 Suppl 1:I44-I53; Storm et al., “MALDI-TOFmass spectrometry-based SNP genotyping”, Methods Mol Biol. 2003;212:241-62; Jurinke et al., “The use of Mass ARRAY technology for highthroughput genotyping”, Adv Biochem Eng Biotechnol. 2002; 77:57-74; andJurinke et al., “Automated genotyping using the DNA MassArraytechnology”, Methods Mol Biol. 2002; 187:179-92.

SNPs can also be scored by direct DNA sequencing. A variety of automatedsequencing procedures can be utilized ((1995) Biotechniques 19:448),including sequencing by mass spectrometry (see, e.g., PCT InternationalPublication No. WO94/16101; Cohen et al., Adv. Chromatogr. 36:127-162(1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159(1993)). The nucleic acid sequences of the present invention enable oneof ordinary skill in the art to readily design sequencing primers forsuch automated sequencing procedures. Commercial instrumentation, suchas the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1 DNAAnalyzers (Foster City, Calif.), is commonly used in the art forautomated sequencing.

Other methods that can be used to genotype the SNPs of the presentinvention include single-strand conformational polymorphism (SSCP), anddenaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature313:495 (1985)). SSCP identifies base differences by alteration inelectrophoretic migration of single stranded PCR products, as describedin Orita et al., Proc. Nat. Acad. Single-stranded PCR products can begenerated by heating or otherwise denaturing double stranded PCRproducts. Single-stranded nucleic acids may refold or form secondarystructures that are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts are related to base-sequence differences at SNP positions. DGGEdifferentiates SNP alleles based on the different sequence-dependentstabilities and melting properties inherent in polymorphic DNA and thecorresponding differences in electrophoretic migration patterns in adenaturing gradient gel (Erlich, ed., PCR Technology, Principles andApplications for DNA Amplification, W.H. Freeman and Co, New York, 1992,Chapter 7).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be usedto score SNPs based on the development or loss of a ribozyme cleavagesite. Perfectly matched sequences can be distinguished from mismatchedsequences by nuclease cleavage digestion assays or by differences inmelting temperature. If the SNP affects a restriction enzyme cleavagesite, the SNP can be identified by alterations in restriction enzymedigestion patterns, and the corresponding changes in nucleic acidfragment lengths determined by gel electrophoresis

SNP genotyping can include the steps of, for example, collecting abiological sample from a human subject (e.g., sample of tissues, cells,fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA,mRNA or both) from the cells of the sample, contacting the nucleic acidswith one or more primers which specifically hybridize to a region of theisolated nucleic acid containing a target SNP under conditions such thathybridization and amplification of the target nucleic acid regionoccurs, and determining the nucleotide present at the SNP position ofinterest, or, in some assays, detecting the presence or absence of anamplification product (assays can be designed so that hybridizationand/or amplification will only occur if a particular SNP allele ispresent or absent). In some assays, the size of the amplificationproduct is detected and compared to the length of a control sample; forexample, deletions and insertions can be detected by a change in size ofthe amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, asdescribed below. Examples of such applications include, but are notlimited to, SNP-disease association analysis, disease predispositionscreening, disease diagnosis, disease prognosis, disease progressionmonitoring, determining therapeutic strategies based on an individual'sgenotype (“pharmacogenomics”), developing therapeutic agents based onSNP genotypes associated with a disease or likelihood of responding to adrug, stratifying a patient population for clinical trial for atreatment regimen, predicting the likelihood that an individual willexperience toxic side effects from a therapeutic agent, and humanidentification applications such as forensics.

Analysis of Genetic Association Between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening,disease prognosis, determining drug responsiveness (pharmacogenomics),drug toxicity screening, and other uses described herein, typicallyrelies on initially establishing a genetic association between one ormore specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies(Modern Epidemiology, Lippincott Williams & Wilkins (1998), 609-622).Observational studies are most frequently carried out in which theresponse of the patients is not interfered with. The first type ofobservational study identifies a sample of persons in whom the suspectedcause of the disease is present and another sample of persons in whomthe suspected cause is absent, and then the frequency of development ofdisease in the two samples is compared. These sampled populations arecalled cohorts, and the study is a prospective study. The other type ofobservational study is case-control or a retrospective study. In typicalcase-control studies, samples are collected from individuals with thephenotype of interest (cases) such as certain manifestations of adisease, and from individuals without the phenotype (controls) in apopulation (target population) that conclusions are to be drawn from.Then the possible causes of the disease are investigatedretrospectively. As the time and costs of collecting samples incase-control studies are considerably less than those for prospectivestudies, case-control studies are the more commonly used study design ingenetic association studies, at least during the exploration anddiscovery stage.

In both types of observational studies, there may be potentialconfounding factors that should be taken into consideration. Confoundingfactors are those that are associated with both the real cause(s) of thedisease and the disease itself, and they include demographic informationsuch as age, gender, ethnicity as well as environmental factors. Whenconfounding factors are not matched in cases and controls in a study,and are not controlled properly, spurious association results can arise.If potential confounding factors are identified, they should becontrolled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is acertain allele or a SNP or a combination of alleles or a haplotype fromseveral SNPs. Thus, tissue specimens (e.g., whole blood) from thesampled individuals may be collected and genomic DNA genotyped for theSNP(s) of interest. In addition to the phenotypic trait of interest,other information such as demographic (e.g., age, gender, ethnicity,etc.), clinical, and environmental information that may influence theoutcome of the trait can be collected to further characterize and definethe sample set. In many cases, these factors are known to be associatedwith diseases and/or SNP allele frequencies. There are likelygene-environment and/or gene-gene interactions as well. Analysis methodsto address gene-environment and gene-gene interactions (for example, theeffects of the presence of both susceptibility alleles at two differentgenes can be greater than the effects of the individual alleles at twogenes combined) are discussed below.

After all the relevant phenotypic and genotypic information has beenobtained, statistical analyses are carried out to determine if there isany significant correlation between the presence of an allele or agenotype with the phenotypic characteristics of an individual.Preferably, data inspection and cleaning are first performed beforecarrying out statistical tests for genetic association. Epidemiologicaland clinical data of the samples can be summarized by descriptivestatistics with tables and graphs. Data validation is preferablyperformed to check for data completion, inconsistent entries, andoutliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests ifdistributions are not normal) may then be used to check for significantdifferences between cases and controls for discrete and continuousvariables, respectively. To ensure genotyping quality, Hardy-Weinbergdisequilibrium tests can be performed on cases and controls separately.Significant deviation from Hardy-Weinberg equilibrium (HWE) in bothcases and controls for individual markers can be indicative ofgenotyping errors. If HWE is violated in a majority of markers, it isindicative of population substructure that should be furtherinvestigated. Moreover, Hardy-Weinberg disequilibrium in cases only canindicate genetic association of the markers with the disease (GeneticData Analysis, Weir B., Sinauer (1990)).

To test whether an allele of a single SNP is associated with the case orcontrol status of a phenotypic trait, one skilled in the art can compareallele frequencies in cases and controls. Standard chi-squared tests andFisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2outcomes in the categorical trait of interest). To test whethergenotypes of a SNP are associated, chi-squared tests can be carried outon a 3×2 table (3 genotypes×2 outcomes). Score tests are also carriedout for genotypic association to contrast the three genotypicfrequencies (major homozygotes, heterozygotes and minor homozygotes) incases and controls, and to look for trends using 3 different modes ofinheritance, namely dominant (with contrast coefficients 2, −1, −1),additive (with contrast coefficients 1, 0, −1) and recessive (withcontrast coefficients 1, 1, −2). Odds ratios for minor versus majoralleles, and odds ratios for heterozygote and homozygote variants versusthe wild type genotypes are calculated with the desired confidencelimits, usually 95%.

In order to control for confounders and to test for interaction andeffect modifiers, stratified analyses may be performed using stratifiedfactors that are likely to be confounding, including demographicinformation such as age, ethnicity, and gender, or an interactingelement or effect modifier, such as a known major gene (e.g., APOE forAlzheimer's disease or HLA genes for autoimmune diseases), orenvironmental factors such as smoking in lung cancer. Stratifiedassociation tests may be carried out using Cochran-Mantel-Haenszel teststhat take into account the ordinal nature of genotypes with 0, 1, and 2variant alleles. Exact tests by StatXact may also be performed whencomputationally possible. Another way to adjust for confounding effectsand test for interactions is to perform stepwise multiple logisticregression analysis using statistical packages such as SAS or R.Logistic regression is a model-building technique in which the bestfitting and most parsimonious model is built to describe the relationbetween the dichotomous outcome (for instance, getting a certain diseaseor not) and a set of independent variables (for instance, genotypes ofdifferent associated genes, and the associated demographic andenvironmental factors). The most common model is one in which the logittransformation of the odds ratios is expressed as a linear combinationof the variables (main effects) and their cross-product terms(interactions) (Applied Logistic Regression, Hosmer and Lemeshow, Wiley(2000)). To test whether a certain variable or interaction issignificantly associated with the outcome, coefficients in the model arefirst estimated and then tested for statistical significance of theirdeparture from zero.

In addition to performing association tests one marker at a time,haplotype association analysis may also be performed to study a numberof markers that are closely linked together. Haplotype association testscan have better power than genotypic or allelic association tests whenthe tested markers are not the disease-causing mutations themselves butare in linkage disequilibrium with such mutations. The test will even bemore powerful if the disease is indeed caused by a combination ofalleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs thatare very close to each other). In order to perform haplotype associationeffectively, marker-marker linkage disequilibrium measures, both D′ andr², are typically calculated for the markers within a gene to elucidatethe haplotype structure. Recent studies (Daly et al, Nature Genetics,29, 232-235, 2001) in linkage disequilibrium indicate that SNPs within agene are organized in block pattern, and a high degree of linkagedisequilibrium exists within blocks and very little linkagedisequilibrium exists between blocks. Haplotype association with thedisease status can be performed using such blocks once they have beenelucidated.

Haplotype association tests can be carried out in a similar fashion asthe allelic and genotypic association tests. Each haplotype in a gene isanalogous to an allele in a multi-allelic marker. One skilled in the artcan either compare the haplotype frequencies in cases and controls ortest genetic association with different pairs of haplotypes. It has beenproposed (Schaid et al, Am. J. Hum. Genet., 70, 425-434, 2002) thatscore tests can be done on haplotypes using the program “haplo.score.”In that method, haplotypes are first inferred by EM algorithm and scoretests are carried out with a generalized linear model (GLM) frameworkthat allows the adjustment of other factors.

An important decision in the performance of genetic association tests isthe determination of the significance level at which significantassociation can be declared when the P value of the tests reaches thatlevel. In an exploratory analysis where positive hits will be followedup in subsequent confirmatory testing, an unadjusted P value<0.2 (asignificance level on the lenient side), for example, may be used forgenerating hypotheses for significant association of a SNP with certainphenotypic characteristics of a disease. It is preferred that ap-value<0.05 (a significance level traditionally used in the art) isachieved in order for a SNP to be considered to have an association witha disease. It is more preferred that a p-value<0.01 (a significancelevel on the stringent side) is achieved for an association to bedeclared. When hits are followed up in confirmatory analyses in moresamples of the same source or in different samples from differentsources, adjustment for multiple testing will be performed as to avoidexcess number of hits while maintaining the experiment-wide error ratesat 0.05. While there are different methods to adjust for multipletesting to control for different kinds of error rates, a commonly usedbut rather conservative method is Bonferroni correction to control theexperiment-wise or family-wise error rate (Multiple comparisons andmultiple tests, Westfall et al, SAS Institute (1999)). Permutation teststo control for the false discovery rates, FDR, can be more powerful(Benjamini and Hochberg, Journal of the Royal Statistical Society,Series B 57, 1289-1300, 1995, Resampling-based Multiple Testing,Westfall and Young, Wiley (1993)). Such methods to control formultiplicity would be preferred when the tests are dependent andcontrolling for false discovery rates is sufficient as opposed tocontrolling for the experiment-wise error rates.

In replication studies using samples from different populations afterstatistically significant markers have been identified in theexploratory stage, meta-analyses can then be performed by combiningevidence of different studies (Modern Epidemiology, Lippincott Williams& Wilkins, 1998, 643-673). If available, association results known inthe art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involveerrors, sensitivity analyses may be performed to see how odds ratios andp-values would change upon various estimates on genotyping and diseaseclassification error rates.

It has been well known that subpopulation-based sampling bias betweencases and controls can lead to spurious results in case-controlassociation studies (Ewens and Spielman, Am. J. Hum. Genet. 62, 450-458,1995) when prevalence of the disease is associated with differentsubpopulation groups. Such bias can also lead to a loss of statisticalpower in genetic association studies. To detect populationstratification, Pritchard and Rosenberg (Pritchard et al. Am. J. Hum.Gen. 1999, 65:220-228) suggested typing markers that are unlinked to thedisease and using results of association tests on those markers todetermine whether there is any population stratification. Whenstratification is detected, the genomic control (GC) method as proposedby Devlin and Roeder (Devlin et al. Biometrics 1999, 55:997-1004) can beused to adjust for the inflation of test statistics due to populationstratification. GC method is robust to changes in population structurelevels as well as being applicable to DNA pooling designs (Devlin et al.Genet. Epidem. 20001, 21:273-284).

While Pritchard's method recommended using 15-20 unlinked microsatellitemarkers, it suggested using more than 30 biallelic markers to get enoughpower to detect population stratification. For the GC method, it hasbeen shown (Bacanu et al. Am. J. Hum. Genet. 2000, 66:1933-1944) thatabout 60-70 biallelic markers are sufficient to estimate the inflationfactor for the test statistics due to population stratification. Hence,70 intergenic SNPs can be chosen in unlinked regions as indicated in agenome scan (Kehoe et al. Hum. Mol. Genet. 1999, 8:237-245).

Once individual risk factors, genetic or non-genetic, have been foundfor the predisposition to disease, the next step is to set up aclassification/prediction scheme to predict the category (for instance,disease or no-disease) that an individual will be in depending on hisgenotypes of associated SNPs and other non-genetic risk factors.Logistic regression for discrete trait and linear regression forcontinuous trait are standard techniques for such tasks (AppliedRegression Analysis, Draper and Smith, Wiley (1998)). Moreover, othertechniques can also be used for setting up classification. Suchtechniques include, but are not limited to, MART, CART, neural network,and discriminant analyses that are suitable for use in comparing theperformance of different methods (The Elements of Statistical Learning,Hastie, Tibshirani & Friedman, Springer (2002)).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes anddisease-related phenotypes can be exploited in several ways. Forexample, in the case of a highly statistically significant associationbetween one or more SNPs with predisposition to a disease for whichtreatment is available, detection of such a genotype pattern in anindividual may justify immediate administration of treatment, or atleast the institution of regular monitoring of the individual. Detectionof the susceptibility alleles associated with serious disease in acouple contemplating having children may also be valuable to the couplein their reproductive decisions. In the case of a weaker but stillstatistically significant association between a SNP and a human disease,immediate therapeutic intervention or monitoring may not be justifiedafter detecting the susceptibility allele or SNP. Nevertheless, thesubject can be motivated to begin simple life-style changes (e.g., diet,exercise) that can be accomplished at little or no cost to theindividual but would confer potential benefits in reducing the risk ofdeveloping conditions for which that individual may have an increasedrisk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development of VT in anindividual in different ways. Some polymorphisms occur within a proteincoding sequence and contribute to disease phenotype by affecting proteinstructure. Other polymorphisms occur in noncoding regions but may exertphenotypic effects indirectly via influence on, for example,replication, transcription, and/or translation. A single SNP may affectmore than one phenotypic trait. Likewise, a single phenotypic trait maybe affected by multiple SNPs in different genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics”include, but are not limited to any of the following: detection of VTthat an individual may presently have, predisposition/susceptibilityscreening (i.e., determining the increased risk of an individual indeveloping VT in the future, or determining whether an individual has adecreased risk of developing VT in the future), determining a particulartype or subclass of VT in an individual known to have VT, confirming orreinforcing a previously made diagnosis of VT, pharmacogenomicevaluation of an individual to determine which therapeutic strategy thatindividual is most likely to positively respond to or to predict whethera patient is likely to respond to a particular treatment, predictingwhether a patient is likely to experience toxic effects from aparticular treatment or therapeutic compound, and evaluating the futureprognosis of an individual having VT. Such diagnostic uses are based onthe SNPs individually or in a unique combination or SNP haplotypes ofthe present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs canbe genotyped to determine if a particular genomic region harbors a locusthat influences a particular phenotype, such as in linkagedisequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles(e.g., alternative nucleotides) at two or more different SNP sites atfrequencies greater than would be expected from the separate frequenciesof occurrence of each allele in a given population. The expectedfrequency of co-occurrence of two alleles that are inheritedindependently is the frequency of the first allele multiplied by thefrequency of the second allele. Alleles that co-occur at expectedfrequencies are said to be in “linkage equilibrium.” In contrast, LDrefers to any non-random genetic association between allele(s) at two ormore different SNP sites, which is generally due to the physicalproximity of the two loci along a chromosome. LD can occur when two ormore SNPs sites are in close physical proximity to each other on a givenchromosome and therefore alleles at these SNP sites will tend to remainunseparated for multiple generations with the consequence that aparticular nucleotide (allele) at one SNP site will show a non-randomassociation with a particular nucleotide (allele) at a different SNPsite located nearby. Hence, genotyping one of the SNP sites will givealmost the same information as genotyping the other SNP site that is inLD.

Various degrees of LD can be encountered between two or more SNPs withthe result being that some SNPs are more closely associated (i.e., instronger LD) than others. Furthermore, the physical distance over whichLD extends along a chromosome differs between different regions of thegenome, and therefore the degree of physical separation between two ormore SNP sites necessary for LD to occur can differ between differentregions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site isfound to be useful for diagnosing VT (e.g., has a significantstatistical association with the condition and/or is recognized as acausative polymorphism for the condition), then the skilled artisanwould recognize that other SNP sites which are in LD with this SNP sitewould also be useful for diagnosing the condition. Thus, polymorphisms(e.g., SNPs and/or haplotypes) that are not the actual disease-causing(causative) polymorphisms, but are in LD with such causativepolymorphisms, are also useful. In such instances, the genotype of thepolymorphism(s) that is/are in LD with the causative polymorphism ispredictive of the genotype of the causative polymorphism and,consequently, predictive of the phenotype (e.g., VT) that is influencedby the causative SNP(s). Therefore, polymorphic markers that are in LDwith causative polymorphisms are useful as diagnostic markers, and areparticularly useful when the actual causative polymorphism(s) is/areunknown.

Examples of polymorphisms that can be in LD with one or more causativepolymorphisms (and/or in LD with one or more polymorphisms that have asignificant statistical association with a condition) and thereforeuseful for diagnosing the same condition that the causative/associatedSNP(s) is used to diagnose, include other SNPs in the same gene,protein-coding, or mRNA transcript-coding region as thecausative/associated SNP, other SNPs in the same exon or same intron asthe causative/associated SNP, other SNPs in the same haplotype block asthe causative/associated SNP, other SNPs in the same intergenic regionas the causative/associated SNP, SNPs that are outside but near a gene(e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) thatharbors a causative/associated SNP, etc. Such useful LD SNPs can beselected from among the SNPs disclosed in Tables 1-2, for example.

Linkage disequilibrium in the human genome is reviewed in: Wall et al.,“Haplotype blocks and linkage disequilibrium in the human genome”, NatRev Genet. 2003 August; 4(8):587-97; Garner et al., “On selectingmarkers for association studies: patterns of linkage disequilibriumbetween two and three diallelic loci”, Genet Epidemiol. 2003 January;24(1):57-67; Ardlie et al., “Patterns of linkage disequilibrium in thehuman genome”, Nat Rev Genet. 2002 April; 3(4):299-309 (erratum in NatRev Genet 2002 July; 3(7):566); and Remm et al., “High-densitygenotyping and linkage disequilibrium in the human genome usingchromosome 22 as a model”; Curr Opin Chem Biol. 2002 February;6(1):24-30; Haldane J B S (1919) The combination of linkage values, andthe calculation of distances between the loci of linked factors. JGenet. 8:299-309; Mendel, G. (1866) Versuche über Pflanzen-Hybriden.Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of theNatural History Society of Brünn]; Lewin B (1990) Genes IV. OxfordUniversity Press, New York, USA; Hartl D L and Clark A G (1989)Principles of Population Genetics 2^(nd) ed. Sinauer Associates, Inc.Sunderland, Mass., USA; Gillespie J H (2004) Population Genetics: AConcise Guide. 2^(nd) ed. Johns Hopkins University Press. USA; LewontinR C (1964). The interaction of selection and linkage. I. Generalconsiderations; heterotic models. Genetics 49:49-67; Hoel P G (1954)Introduction to Mathematical Statistics 2^(nd) ed. John Wiley & Sons,Inc. New York, USA; Hudson R R (2001) Two-locus sampling distributionsand their application. Genetics 159:1805-1817; Dempster A P, Laird N M,Rubin D B (1977) Maximum likelihood from incomplete data via the EMalgorithm. J R Stat Soc 39:1-38; Excoffier L, Slatkin M (1995)Maximum-likelihood estimation of molecular haplotype frequencies in adiploid population. Mol Biol Evol 12(5):921-927; Tregouet D A, EscolanoS, Tiret L, Mallet A, Golmard J L (2004) A new algorithm forhaplotype-based association analysis: the Stochastic-EM algorithm. AnnHum Genet. 68(Pt 2):165-177; Long A D and Langley C H (1999) The powerof association studies to detect the contribution of candidate geneticloci to variation in complex traits. Genome Research 9:720-731; AgrestiA (1990) Categorical Data Analysis. John Wiley & Sons, Inc. New York,USA; Lange K (1997) Mathematical and Statistical Methods for GeneticAnalysis. Springer-Verlag New York, Inc. New York, USA; TheInternational HapMap Consortium (2003) The International HapMap Project.Nature 426:789-796; The International HapMap Consortium (2005) Ahaplotype map of the human genome. Nature 437:1299-1320; Thorisson G A,Smith A V, Krishnan L, Stein L D (2005), The International HapMapProject Web Site. Genome Research 15:1591-1593; McVean G, Spencer C C A,Chaix R (2005) Perspectives on human genetic variation from the HapMapproject. PLoS Genetics 1(4):413-418; Hirschhorn J N, Daly M J (2005)Genome-wide association studies for common diseases and complex traits.Nat Genet 6:95-108; Schrodi S J (2005) A probabilistic approach tolarge-scale association scans: a semi-Bayesian method to detectdisease-predisposing alleles. SAGMB 4(1):31; Wang W Y S, Barratt B J,Clayton D G, Todd J A (2005) Genome-wide association studies:theoretical and practical concerns. Nat Rev Genet 6:109-118. Pritchard JK, Przeworski M (2001) Linkage disequilibrium in humans: models anddata. Am J Hum Genet 69:1-14.

As discussed above, one aspect of the present invention is the discoverythat SNPs which are in certain LD distance with the interrogated SNP canalso be used as valid markers for identifying an increased or decreasedrisks of having or developing VT. As used herein, the term “interrogatedSNP” refers to SNPs that have been found to be associated with anincreased or decreased risk of disease using genotyping results andanalysis, or other appropriate experimental method as exemplified in theworking examples described in this application. As used herein, the term“LD SNP” refers to a SNP that has been characterized as a SNPassociating with an increased or decreased risk of diseases due to theirbeing in LD with the “interrogated SNP” under the methods of calculationdescribed in the application. Below, applicants describe the methods ofcalculation with which one of ordinary skilled in the art may determineif a particular SNP is in LD with an interrogated SNP. The parameter r²is commonly used in the genetics art to characterize the extent oflinkage disequilibrium between markers (Hudson, 2001). As used herein,the term “in LD with” refers to a particular SNP that is measured atabove the threshold of a parameter such as r² with an interrogated SNP.

The r² value between any two or more SNPs can be obtained from databasessuch as the HapMap. For instance, if the r² value between SNP1 and SNP2is 0.8 (assuming 0.8 is used as a threshold), then these two SNPs are inLD with each other, thus leading one to conclude that if SNP1 isassociated with a disease, then SNP2 will be associated with the diseaseas well.

It is now common place to directly observe genetic variants in a sampleof chromosomes obtained from a population. Suppose one has genotype dataat two genetic markers located on the same chromosome, for the markers Aand B. Further suppose that two alleles segregate at each of these twomarkers such that alleles A₁ and A₂ can be found at marker A and allelesB₁ and B₂ at marker B. Also assume that these two markers are on a humanautosome. If one is to examine a specific individual and find that theyare heterozygous at both markers, such that their two-marker genotype isA₁A₂B₁B₂, then there are two possible configurations: the individual inquestion could have the alleles A₁B₁ on one chromosome and A₂B₂ on theremaining chromosome; alternatively, the individual could have allelesA₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleleson a chromosome is called a haplotype. In this illustration, theindividual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl andClark (1989) for a more complete description). The concept of linkageequilibrium relates the frequency of haplotypes to the allelefrequencies.

Assume that a sample of individuals is selected from a largerpopulation. Considering the two markers described above, each having twoalleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂.Denote the frequencies of these four haplotypes with the followingnotation.

P ₁₁=freq(A ₁ B ₁)  (1)

P ₁₂=freq(A ₁ B ₂)  (2)

P ₂₁=freq(A ₂ B ₁)  (3)

P ₂₂=freq(A ₂ B ₂)  (4)

The allele frequencies at the two markers are then the sum of differenthaplotype frequencies, it is straightforward to write down a similar setof equations relating single-marker allele frequencies to two-markerhaplotype frequencies:

p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)

p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)

q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7)

q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)

Note that the four haplotype frequencies and the allele frequencies ateach marker must sum to a frequency of 1.

P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)

p ₁ +p ₂=1  (10)

q ₁ +q ₂=1  (11)

If there is no correlation between the alleles at the two markers, onewould expect that the frequency of the haplotypes would be approximatelythe product of the composite alleles. Therefore,

P₁₁≈p₁q₁  (12)

P₁₂≈p₁q₂  (13)

P₂₁≈p₂q₁  (14)

P₂₂≈p₂q₂  (15)

These approximating equations (12)-(15) represent the concept of linkageequilibrium where there is independent assortment between the twomarkers—the alleles at the two markers occur together at random. Theseare represented as approximations because linkage equilibrium andlinkage disequilibrium are concepts typically thought of as propertiesof a sample of chromosomes; and as such they are susceptible tostochastic fluctuations due to the sampling process. Empirically, manypairs of genetic markers will be in linkage equilibrium, but certainlynot all pairs.

Having established the concept of linkage equilibrium above, applicantscan now describe the concept of linkage disequilibrium (LD), which isthe deviation from linkage equilibrium. Since the frequency of the A₁B₁haplotype is approximately the product of the allele frequencies for A₁and B₁ under the assumption of linkage equilibrium as statedmathematically in (12), a simple measure for the amount of departurefrom linkage equilibrium is the difference in these two quantities, D,

D=P ₁₁ −p ₁ q ₁  (16)

D=0 indicates perfect linkage equilibrium. Substantial departures fromD=0 indicates LD in the sample of chromosomes examined. Many propertiesof D are discussed in Lewontin (1964) including the maximum and minimumvalues that D can take. Mathematically, using basic algebra, it can beshown that D can also be written solely in terms of haplotypes:

D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17)

If one transforms D by squaring it and subsequently dividing by theproduct of the allele frequencies of A₁, A₂, B₁ and B₂, the resultingquantity, called r², is equivalent to the square of the Pearson'scorrelation coefficient commonly used in statistics (e.g. Hoel, 1954).

$\begin{matrix}{r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18)\end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium betweenthe two markers examined in the sample set. As values of r² increase,the two markers are said to be in linkage disequilibrium. The range ofvalues that r² can take are from 0 to 1. r²=1 when there is a perfectcorrelation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And assuch, it is necessary to formulate notation specific to the samplesstudied. In the approach discussed here, three types of samples are ofprimary interest: (i) a sample of chromosomes from individuals affectedby a disease-related phenotype (cases), (ii) a sample of chromosomesobtained from individuals not affected by the disease-related phenotype(controls), and (iii) a standard sample set used for the construction ofhaplotypes and calculation pairwise linkage disequilibrium. For theallele frequencies used in the development of the method describedbelow, an additional subscript will be added to denote either the caseor control sample sets.

p _(1,cs)=freq(A ₁in cases)  (19)

p _(2,cs)=freq(A ₂in cases)  (20)

q _(1,cs)=freq(B ₁in cases)  (21)

q _(2,cs)=freq(B ₂in cases)  (22)

Similarly,

p _(1,ct)=freq(A ₁in controls)  (23)

p _(2,ct)=freq(A ₂in controls)  (24)

q _(1,ct)=freq(B ₁in controls)  (25)

q _(2,ct)=freq(B ₂in controls)  (26)

As a well-accepted sample set is necessary for robust linkagedisequilibrium calculations, data obtained from the International HapMapproject (The International HapMap Consortium 2003, 2005; Thorisson etal, 2005; McVean et al, 2005) can be used for the calculation ofpairwise r² values. Indeed, the samples genotyped for the InternationalHapMap Project were selected to be representative examples from varioushuman sub-populations with sufficient numbers of chromosomes examined todraw meaningful and robust conclusions from the patterns of geneticvariation observed. The International HapMap project website(hapmap.org) contains a description of the project, methods utilized andsamples examined. It is useful to examine empirical data to get a senseof the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.However, knowing the 2-marker haplotype frequencies requires that phaseto be determined for doubly heterozygous samples. When phase is unknownin the data examined, various algorithms can be used to infer phase fromthe genotype data. This issue was discussed earlier where the doublyheterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have oneof two different sets of chromosomes: A₁B₁/A₂B₂ or A₁B₂/A₂B₁. One suchalgorithm to estimate haplotype frequencies is theexpectation-maximization (EM) algorithm first formalized by Dempster etal (1977). This algorithm is often used in genetics to infer haplotypefrequencies from genotype data (e.g. Excoffier and Slatkin, 1995;Tregouet et al, 2004). It should be noted that for the two-SNP caseexplored here, EM algorithms have very little error provided that theallele frequencies and sample sizes are not too small. The impact on r²values is typically negligible.

As correlated genetic markers share information, interrogation of SNPmarkers in LD with a disease-associated SNP marker can also havesufficient power to detect disease association (Long and Langley, 1999).The relationship between the power to directly find disease-associatedalleles and the power to indirectly detect disease-association wasinvestigated by Pritchard and Przeworski (2001). In a straight-forwardderivation, it can be shown that the power to detect disease associationindirectly at a marker locus in linkage disequilibrium with adisease-association locus is approximately the same as the power todetect disease-association directly at the disease-association locus ifthe sample size is increased by a factor of

$\frac{1}{r^{2}}$

(the reciprocal of equation 18) at the marker in comparison with thedisease-association locus.

Therefore, if one calculated the power to detect disease-associationindirectly with an experiment having N samples, then equivalent power todirectly detect disease-association (at the actualdisease-susceptibility locus) would necessitate an experiment usingapproximately r²N samples. This elementary relationship between power,sample size and linkage disequilibrium can be used to derive an r²threshold value useful in determining whether or not genotyping markersin linkage disequilibrium with a SNP marker directly associated withdisease status has enough power to indirectly detectdisease-association.

To commence a derivation of the power to detect disease-associatedmarkers through an indirect process, define the effective chromosomalsample size as

$\begin{matrix}{{n = \frac{4N_{cs}N_{ct}}{N_{cs} + N_{ct}}};} & (27)\end{matrix}$

where N_(cs) and N_(ct) are the numbers of diploid cases and controls,respectively. This is necessary to handle situations where the numbersof cases and controls are not equivalent. For equal case and controlsample sizes, N_(cs)=N_(ct)=N, the value of the effective number ofchromosomes is simply n=2N—as expected. Let power be calculated for asignificance level α (such that traditional P-values below α will bedeemed statistically significant). Define the standard Gaussiandistribution function as Φ(•). Mathematically,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{\sqrt{2\; \pi}}{\int_{- \infty}^{x}{^{- \frac{\theta^{2}}{2}}\ {\theta}}}}} & (28)\end{matrix}$

Alternatively, the following error function notation (Erf) may also beused,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}} & (29)\end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield apre-specified minimum amount of power to detect disease associationthough indirect interrogation. Noting that the LD SNP marker could bethe one that is carrying the disease-association allele, therefore thatthis approach constitutes a lower-bound model where all indirect powerresults are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associatedmarkers. Therefore, 1−β is the classical definition of statisticalpower. Substituting the Pritchard-Pzreworski result into the samplesize, the power to detect disease association at a significance level ofα is given by the approximation

$\begin{matrix}{{{1 - \beta} \cong {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}};} & (30)\end{matrix}$

where Z_(u) is the inverse of the standard normal cumulativedistribution evaluated at U (uε(0,1)). Z_(u)=Φ⁻¹(u), whereΦ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore1−^(α)/₂=0.975, Z_(0.975)=1.95996 is obtained. Next, setting power equalto a threshold of a minimum power of T,

$\begin{matrix}{T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}} & (31)\end{matrix}$

and solving for r², the following threshold r² is obtained:

$\begin{matrix}{{r_{T}^{2} = {\frac{\left\lbrack {{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rbrack}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - {\alpha/2}}} \right\rbrack}}{{Or},}} & (32) \\{r_{T}^{2} = {\left( \frac{Z_{T} + Z_{1 - {\alpha/2}}}{n} \right)\left\lbrack \frac{q_{1,{cs}} - \left( q_{1,{cs}} \right)^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{1,{ct}}} \right)^{2}} \right\rbrack}} & (33)\end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a numberof other SNPs with varying levels of LD with the interrogated SNP. Thethreshold value r_(T) ² is the minimum value of linkage disequilibriumbetween the interrogated SNP and the potential LD SNPs such that the LDSNP still retains a power greater or equal to T for detectingdisease-association. For example, suppose that SNP rs200 is genotyped ina case-control disease-association study and it is found to beassociated with a disease phenotype. Further suppose that the minorallele frequency in 1,000 case chromosomes was found to be 16% incontrast with a minor allele frequency of 10% in 1,000 controlchromosomes. Given those measurements one could have predicted, prior tothe experiment, that the power to detect disease association at asignificance level of 0.05 was quite high—approximately 98% using a testof allelic association. Applying equation (32) one can calculate aminimum value of r² to indirectly assess disease association assumingthat the minor allele at SNP rs200 is truly disease-predisposing for athreshold level of power. If one sets the threshold level of power to be80%, then r_(T) ²=0.489 given the same significance level and chromosomenumbers as above. Hence, any SNP with a pairwise r² value with rs200greater than 0.489 is expected to have greater than 80% power to detectthe disease association. Further, this is assuming the conservativemodel where the LD SNP is disease-associated only through linkagedisequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypeswith disease phenotypes, such as VT, enables the SNPs of the presentinvention to be used to develop superior diagnostic tests capable ofidentifying individuals who express a detectable trait, such as VT, asthe result of a specific genotype, or individuals whose genotype placesthem at an increased or decreased risk of developing a detectable traitat a subsequent time as compared to individuals who do not have thatgenotype. As described herein, diagnostics may be based on a single SNPor a group of SNPs. Combined detection of a plurality of SNPs (forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between,or more, of the SNPs provided in Table 1 and/or Table 2) typicallyincreases the probability of an accurate diagnosis. For example, thepresence of a single SNP known to correlate with VT might indicate aprobability of 20% that an individual has or is at risk of developingVT, whereas detection of five SNPs, each of which correlates with VT,might indicate a probability of 80% that an individual has or is at riskof developing VT. To further increase the accuracy of diagnosis orpredisposition screening, analysis of the SNPs of the present inventioncan be combined with that of other polymorphisms or other risk factorsof VT, such as disease symptoms, pathological characteristics, familyhistory, diet, environmental factors or lifestyle factors.

It will, of course, be understood by practitioners skilled in thetreatment or diagnosis of VT that the present invention generally doesnot intend to provide an absolute identification of individuals who areat risk (or less at risk) of developing VT, and/or pathologies relatedto VT, but rather to indicate a certain increased (or decreased) degreeor likelihood of developing the disease based on statisticallysignificant association results. However, this information is extremelyvaluable as it can be used to, for example, initiate preventivetreatments or to allow an individual carrying one or more significantSNPs or SNP haplotypes to foresee warning signs such as minor clinicalsymptoms, or to have regularly scheduled physical exams to monitor forappearance of a condition in order to identify and begin treatment ofthe condition at an early stage. Particularly with diseases that areextremely debilitating or fatal if not treated on time, the knowledge ofa potential predisposition, even if this predisposition is not absolute,would likely contribute in a very significant manner to treatmentefficacy.

The diagnostic techniques of the present invention may employ a varietyof methodologies to determine whether a test subject has a SNP or a SNPpattern associated with an increased or decreased risk of developing adetectable trait or whether the individual suffers from a detectabletrait as a result of a particular polymorphism/mutation, including, forexample, methods which enable the analysis of individual chromosomes forhaplotyping, family studies, single sperm DNA analysis, or somatichybrids. The trait analyzed using the diagnostics of the invention maybe any detectable trait that is commonly observed in pathologies anddisorders related to VT.

Another aspect of the present invention relates to a method ofdetermining whether an individual is at risk (or less at risk) ofdeveloping one or more traits or whether an individual expresses one ormore traits as a consequence of possessing a particular trait-causing ortrait-influencing allele. These methods generally involve obtaining anucleic acid sample from an individual and assaying the nucleic acidsample to determine which nucleotide(s) is/are present at one or moreSNP positions, wherein the assayed nucleotide(s) is/are indicative of anincreased or decreased risk of developing the trait or indicative thatthe individual expresses the trait as a result of possessing aparticular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the presentinvention are used to determine whether an individual has one or moreSNP allele(s) affecting the level (e.g., the concentration of mRNA orprotein in a sample, etc.) or pattern (e.g., the kinetics of expression,rate of decomposition, stability profile, Km, Vmax, etc.) of geneexpression (collectively, the “gene response” of a cell or bodilyfluid). Such a determination can be accomplished by screening for mRNAor protein expression (e.g., by using nucleic acid arrays, RT-PCR,TaqMan assays, or mass spectrometry), identifying genes having alteredexpression in an individual, genotyping SNPs disclosed in Table 1 and/orTable 2 that could affect the expression of the genes having alteredexpression (e.g., SNPs that are in and/or around the gene(s) havingaltered expression, SNPs in regulatory/control regions, SNPs in and/oraround other genes that are involved in pathways that could affect theexpression of the gene(s) having altered expression, or all SNPs couldbe genotyped), and correlating SNP genotypes with altered geneexpression. In this manner, specific SNP alleles at particular SNP sitescan be identified that affect gene expression.

Pharmacogenomics and Therapeutics/Drug Development

The present invention provides methods for assessing thepharmacogenomics of a subject harboring particular SNP alleles orhaplotypes to a particular therapeutic agent or pharmaceutical compound,or to a class of such compounds. Pharmacogenomics deals with the roleswhich clinically significant hereditary variations (e.g., SNPs) play inthe response to drugs due to altered drug disposition and/or abnormalaction in affected persons. See, e.g., Roses, Nature 405, 857-865(2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001);Eichelbaum, Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 (1996); andLinder, Clin. Chem. 43(2):254-266 (1997). The clinical outcomes of thesevariations can result in severe toxicity of therapeutic drugs in certainindividuals or therapeutic failure of drugs in certain individuals as aresult of individual variation in metabolism. Thus, the SNP genotype ofan individual can determine the way a therapeutic compound acts on thebody or the way the body metabolizes the compound. For example, SNPs indrug metabolizing enzymes can affect the activity of these enzymes,which in turn can affect both the intensity and duration of drug action,as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters,proteins for pharmaceutical agents, and other drug targets has explainedwhy some patients do not obtain the expected drug effects, show anexaggerated drug effect, or experience serious toxicity from standarddrug dosages. SNPs can be expressed in the phenotype of the extensivemetabolizer and in the phenotype of the poor metabolizer. Accordingly,SNPs may lead to allelic variants of a protein in which one or more ofthe protein functions in one population are different from those inanother population. SNPs and the encoded variant peptides thus providetargets to ascertain a genetic predisposition that can affect treatmentmodality. For example, in a ligand-based treatment, SNPs may give riseto amino terminal extracellular domains and/or other ligand-bindingregions of a receptor that are more or less active in ligand binding,thereby affecting subsequent protein activation. Accordingly, liganddosage would necessarily be modified to maximize the therapeutic effectwithin a given population containing particular SNP alleles orhaplotypes.

As an alternative to genotyping, specific variant proteins containingvariant amino acid sequences encoded by alternative SNP alleles could beidentified. Thus, pharmacogenomic characterization of an individualpermits the selection of effective compounds and effective dosages ofsuch compounds for prophylactic or therapeutic uses based on theindividual's SNP genotype, thereby enhancing and optimizing theeffectiveness of the therapy. Furthermore, the production of recombinantcells and transgenic animals containing particular SNPs/haplotypes alloweffective clinical design and testing of treatment compounds and dosageregimens. For example, transgenic animals can be produced that differonly in specific SNP alleles in a gene that is orthologous to a humandisease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provideseveral significant advantages for patient care, particularly intreating VT. Pharmacogenomic characterization of an individual, based onan individual's SNP genotype, can identify those individuals unlikely torespond to treatment with a particular medication and thereby allowsphysicians to avoid prescribing the ineffective medication to thoseindividuals. On the other hand, SNP genotyping of an individual mayenable physicians to select the appropriate medication and dosageregimen that will be most effective based on an individual's SNPgenotype. This information increases a physician's confidence inprescribing medications and motivates patients to comply with their drugregimens. Furthermore, pharmacogenomics may identify patientspredisposed to toxicity and adverse reactions to particular drugs ordrug dosages. Adverse drug reactions lead to more than 100,000 avoidabledeaths per year in the United States alone and therefore represent asignificant cause of hospitalization and death, as well as a significanteconomic burden on the healthcare system (Pfost et. al., Trends inBiotechnology, August 2000.). Thus, pharmacogenomics based on the SNPsdisclosed herein has the potential to both save lives and reducehealthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al.,“Pharmacogenetic analysis of clinically relevant genetic polymorphisms”,Methods Mol Med. 2003; 85:225-37. Pharmacogenomics as it relates toAlzheimer's disease and other neurodegenerative disorders is discussedin Cacabelos, “Pharmacogenomics for the treatment of dementia”, Ann Med.2002; 34(5):357-79, Maimone et al., “Pharmacogenomics ofneurodegenerative diseases”, Eur J. Pharmacol. 2001 Feb. 9; 413(1):11-29, and Poirier, “Apolipoprotein E: a pharmacogenetic target for thetreatment of Alzheimer's disease”, Mol Diagn. 1999 December;4(4):335-41. Pharmacogenomics as it relates to cardiovascular disordersis discussed in Siest et al., “Pharmacogenomics of drugs affecting thecardiovascular system”, Clin Chem Lab Med. 2003 April; 41(4):590-9,Mukherjee et al., “Pharmacogenomics in cardiovascular diseases”, ProgCardiovasc Dis. 2002 May-June; 44(6):479-98, and Mooser et al.,“Cardiovascular pharmacogenetics in the SNP era”, J Thromb Haemost. 2003July; 1(7):1398-402. Pharmacogenomics as it relates to cancer isdiscussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, andthe individual patient”, Cancer Invest. 2003; 21(4):630-40 and Watterset al., “Cancer pharmacogenomics: current and future applications”,Biochim Biophys Acta. 2003 Mar. 17; 1603(2):99-111.

The SNPs of the present invention also can be used to identify noveltherapeutic targets for VT. For example, genes containing thedisease-associated variants (“variant genes”) or their products, as wellas genes or their products that are directly or indirectly regulated byor interacting with these variant genes or their products, can betargeted for the development of therapeutics that, for example, treatthe disease or prevent or delay disease onset. The therapeutics may becomposed of, for example, small molecules, proteins, protein fragmentsor peptides, antibodies, nucleic acids, or their derivatives or mimeticswhich modulate the functions or levels of the target genes or geneproducts.

The SNP-containing nucleic acid molecules disclosed herein, and theircomplementary nucleic acid molecules, may be used as antisenseconstructs to control gene expression in cells, tissues, and organisms.Antisense technology is well established in the art and extensivelyreviewed in Antisense Drug Technology: Principles, Strategies, andApplications, Crooke (ed.), Marcel Dekker, Inc.: New York (2001). Anantisense nucleic acid molecule is generally designed to becomplementary to a region of mRNA expressed by a gene so that theantisense molecule hybridizes to the mRNA and thereby blocks translationof mRNA into protein. Various classes of antisense oligonucleotides areused in the art, two of which are cleavers and blockers. Cleavers, bybinding to target RNAs, activate intracellular nucleases (e.g., RNaseHor RNase L) that cleave the target RNA. Blockers, which also bind totarget RNAs, inhibit protein translation through steric hindrance ofribosomes. Exemplary blockers include peptide nucleic acids,morpholinos, locked nucleic acids, and methylphosphonates (see, e.g.,Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Antisenseoligonucleotides are directly useful as therapeutic agents, and are alsouseful for determining and validating gene function (e.g., in geneknock-out or knock-down experiments).

Antisense technology is further reviewed in: Layery et al., “Antisenseand RNAi: powerful tools in drug target discovery and validation”, CurrOpin Drug Discov Devel. 2003 July; 6(4):561-9; Stephens et al.,“Antisense oligonucleotide therapy in cancer”, Curr Opin Mol Ther. 2003April; 5(2): 118-22; Kurreck, “Antisense technologies. Improvementthrough novel chemical modifications”, Eur J Biochem. 2003 April;270(8):1628-44; Dias et al., “Antisense oligonucleotides: basic conceptsand mechanisms”, Mol Cancer Ther. 2002 March; 1(5):347-55; Chen,“Clinical development of antisense oligonucleotides as anti-cancertherapeutics”, Methods Mol Med. 2003; 75:621-36; Wang et al., “Antisenseanticancer oligonucleotide therapeutics”, Curr Cancer Drug Targets. 2001November; 1(3):177-96; and Bennett, “Efficiency of antisenseoligonucleotide drug discovery”, Antisense Nucleic Acid Drug Dev. 2002June; 12(3):215-24.

The SNPs of the present invention are particularly useful for designingantisense reagents that are specific for particular nucleic acidvariants. Based on the SNP information disclosed herein, antisenseoligonucleotides can be produced that specifically target mRNA moleculesthat contain one or more particular SNP nucleotides. In this manner,expression of mRNA molecules that contain one or more undesiredpolymorphisms (e.g., SNP nucleotides that lead to a defective proteinsuch as an amino acid substitution in a catalytic domain) can beinhibited or completely blocked. Thus, antisense oligonucleotides can beused to specifically bind a particular polymorphic form (e.g., a SNPallele that encodes a defective protein), thereby inhibiting translationof this form, but which do not bind an alternative polymorphic form(e.g., an alternative SNP nucleotide that encodes a protein havingnormal function).

Antisense molecules can be used to inactivate mRNA in order to inhibitgene expression and production of defective proteins. Accordingly, thesemolecules can be used to treat a disorder, such as VT, characterized byabnormal or undesired gene expression or expression of certain defectiveproteins. This technique can involve cleavage by means of ribozymescontaining nucleotide sequences complementary to one or more regions inthe mRNA that attenuate the ability of the mRNA to be translated.Possible mRNA regions include, for example, protein-coding regions andparticularly protein-coding regions corresponding to catalyticactivities, substrate/ligand binding, or other functional activities ofa protein.

The SNPs of the present invention are also useful for designing RNAinterference reagents that specifically target nucleic acid moleculeshaving particular SNP variants. RNA interference (RNAi), also referredto as gene silencing, is based on using double-stranded RNA (dsRNA)molecules to turn genes off. When introduced into a cell, dsRNAs areprocessed by the cell into short fragments (generally about 21, 22, or23 nucleotides in length) known as small interfering RNAs (siRNAs) whichthe cell uses in a sequence-specific manner to recognize and destroycomplementary RNAs (Thompson, Drug Discovery Today, 7 (17): 912-917(2002)). Accordingly, an aspect of the present invention specificallycontemplates isolated nucleic acid molecules that are about 18-26nucleotides in length, preferably 19-25 nucleotides in length, and morepreferably 20, 21, 22, or 23 nucleotides in length, and the use of thesenucleic acid molecules for RNAi. Because RNAi molecules, includingsiRNAs, act in a sequence-specific manner, the SNPs of the presentinvention can be used to design RNAi reagents that recognize and destroynucleic acid molecules having specific SNP alleles/nucleotides (such asdeleterious alleles that lead to the production of defective proteins),while not affecting nucleic acid molecules having alternative SNPalleles (such as alleles that encode proteins having normal function).As with antisense reagents, RNAi reagents may be directly useful astherapeutic agents (e.g., for turning off defective, disease-causinggenes), and are also useful for characterizing and validating genefunction (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds etal., “Rational siRNA design for RNA interference”, Nat Biotechnol. 2004March; 22(3):326-30. Epub 2004 Feb. 1; Chi et al., “Genomewide view ofgene silencing by small interfering RNAs”, PNAS 100(11):6343-6346, 2003;Vickers et al., “Efficient Reduction of Target RNAs by Small InterferingRNA and RNase H-dependent Antisense Agents”, J. Biol. Chem. 278:7108-7118, 2003; Agami, “RNAi and related mechanisms and their potentialuse for therapy”, Curr Opin Chem Biol. 2002 December; 6(6):829-34;Layery et al., “Antisense and RNAi: powerful tools in drug targetdiscovery and validation”, Curr Opin Drug Discov Devel. 2003 July;6(4):561-9; Shi, “Mammalian RNAi for the masses”, Trends Genet 2003January; 19(1):9-12), Shuey et al., “RNAi: gene-silencing in therapeuticintervention”, Drug Discovery Today 2002 October; 7(20): 1040-1046;McManus et al., Nat Rev Genet 2002 October; 3(10):737-47; Xia et al.,Nat Biotechnol 2002 October; 20(10):1006-10; Plasterk et al., Curr OpinGenet Dev 2000 October; 10(5):562-7; Bosher et al., Nat Cell Biol 2000February; 2(2):E31-6; and Hunter, Curr Biol 1999 Jun. 17; 9(12):R440-2).

A subject suffering from a pathological condition, such as VT, ascribedto a SNP may be treated so as to correct the genetic defect (see Kren etal., Proc. Natl. Acad. Sci. USA 96:10349-10354 (1999)). Such a subjectcan be identified by any method that can detect the polymorphism in abiological sample drawn from the subject. Such a genetic defect may bepermanently corrected by administering to such a subject a nucleic acidfragment incorporating a repair sequence that supplies thenormal/wild-type nucleotide at the position of the SNP. Thissite-specific repair sequence can encompass an RNA/DNA oligonucleotidethat operates to promote endogenous repair of a subject's genomic DNA.The site-specific repair sequence is administered in an appropriatevehicle, such as a complex with polyethylenimine, encapsulated inanionic liposomes, a viral vector such as an adenovirus, or otherpharmaceutical composition that promotes intracellular uptake of theadministered nucleic acid. A genetic defect leading to an inbornpathology may then be overcome, as the chimeric oligonucleotides induceincorporation of the normal sequence into the subject's genome. Uponincorporation, the normal gene product is expressed, and the replacementis propagated, thereby engendering a permanent repair and therapeuticenhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribedto be the cause of, or a contributing factor to, a pathologicalcondition, a method of treating such a condition can includeadministering to a subject experiencing the pathology thewild-type/normal cognate of the variant protein. Once administered in aneffective dosing regimen, the wild-type cognate provides complementationor remediation of the pathological condition.

The invention further provides a method for identifying a compound oragent that can be used to treat VT. The SNPs disclosed herein are usefulas targets for the identification and/or development of therapeuticagents. A method for identifying a therapeutic agent or compoundtypically includes assaying the ability of the agent or compound tomodulate the activity and/or expression of a SNP-containing nucleic acidor the encoded product and thus identifying an agent or a compound thatcan be used to treat a disorder characterized by undesired activity orexpression of the SNP-containing nucleic acid or the encoded product.The assays can be performed in cell-based and cell-free systems.Cell-based assays can include cells naturally expressing the nucleicacid molecules of interest or recombinant cells genetically engineeredto express certain nucleic acid molecules.

Variant gene expression in a VT patient can include, for example, eitherexpression of a SNP-containing nucleic acid sequence (for instance, agene that contains a SNP can be transcribed into an mRNA transcriptmolecule containing the SNP, which can in turn be translated into avariant protein) or altered expression of a normal/wild-type nucleicacid sequence due to one or more SNPs (for instance, aregulatory/control region can contain a SNP that affects the level orpattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleicacid levels (e.g., mRNA levels), expressed protein levels, or ofcollateral compounds involved in a signal pathway. Further, theexpression of genes that are up- or down-regulated in response to thesignal pathway can also be assayed. In this embodiment, the regulatoryregions of these genes can be operably linked to a reporter gene such asluciferase.

Modulators of variant gene expression can be identified in a methodwherein, for example, a cell is contacted with a candidatecompound/agent and the expression of mRNA determined. The level ofexpression of mRNA in the presence of the candidate compound is comparedto the level of expression of mRNA in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof variant gene expression based on this comparison and be used to treata disorder such as VT that is characterized by variant gene expression(e.g., either expression of a SNP-containing nucleic acid or alteredexpression of a normal/wild-type nucleic acid molecule due to one ormore SNPs that affect expression of the nucleic acid molecule) due toone or more SNPs of the present invention. When expression of mRNA isstatistically significantly greater in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of nucleic acid expression. When nucleic acid expression isstatistically significantly less in the presence of the candidatecompound than in its absence, the candidate compound is identified as aninhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP orassociated nucleic acid domain (e.g., catalytic domain,ligand/substrate-binding domain, regulatory/control region, etc.) orgene, or the encoded mRNA transcript, as a target, using a compoundidentified through drug screening as a gene modulator to modulatevariant nucleic acid expression. Modulation can include eitherup-regulation (i.e., activation or agonization) or down-regulation(i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type orvariant, may be altered in individuals with a particular SNP allele in aregulatory/control element, such as a promoter or transcription factorbinding domain, that regulates expression. In this situation, methods oftreatment and compounds can be identified, as discussed herein, thatregulate or overcome the variant regulatory/control element, therebygenerating normal, or healthy, expression levels of either the wild typeor variant protein.

The SNP-containing nucleic acid molecules of the present invention arealso useful for monitoring the effectiveness of modulating compounds onthe expression or activity of a variant gene, or encoded product, inclinical trials or in a treatment regimen. Thus, the gene expressionpattern can serve as an indicator for the continuing effectiveness oftreatment with the compound, particularly with compounds to which apatient can develop resistance, as well as an indicator for toxicities.The gene expression pattern can also serve as a marker indicative of aphysiological response of the affected cells to the compound.Accordingly, such monitoring would allow either increased administrationof the compound or the administration of alternative compounds to whichthe patient has not become resistant. Similarly, if the level of nucleicacid expression falls below a desirable level, administration of thecompound could be commensurately decreased.

In another aspect of the present invention, there is provided apharmaceutical pack comprising a therapeutic agent (e.g., a smallmolecule drug, antibody, peptide, antisense or RNAi nucleic acidmolecule, etc.) and a set of instructions for administration of thetherapeutic agent to humans diagnostically tested for one or more SNPsor SNP haplotypes provided by the present invention.

The SNPs/haplotypes of the present invention are also useful forimproving many different aspects of the drug development process. Forinstance, an aspect of the present invention includes selectingindividuals for clinical trials based on their SNP genotype. Forexample, individuals with SNP genotypes that indicate that they arelikely to positively respond to a drug can be included in the trials,whereas those individuals whose SNP genotypes indicate that they areless likely to or would not respond to the drug, or who are at risk forsuffering toxic effects or other adverse reactions, can be excluded fromthe clinical trials. This not only can improve the safety of clinicaltrials, but also can enhance the chances that the trial will demonstratestatistically significant efficacy. Furthermore, the SNPs of the presentinvention may explain why certain previously developed drugs performedpoorly in clinical trials and may help identify a subset of thepopulation that would benefit from a drug that had previously performedpoorly in clinical trials, thereby “rescuing” previously developeddrugs, and enabling the drug to be made available to a particular VTpatient population that can benefit from it.

SNPs have many important uses in drug discovery, screening, anddevelopment. A high probability exists that, for any gene/proteinselected as a potential drug target, variants of that gene/protein willexist in a patient population. Thus, determining the impact ofgene/protein variants on the selection and delivery of a therapeuticagent should be an integral aspect of the drug discovery and developmentprocess. (Jazwinska, A Trends Guide to Genetic Variation and GenomicMedicine, 2002 March; S30-S36).

Knowledge of variants (e.g., SNPs and any corresponding amino acidpolymorphisms) of a particular therapeutic target (e.g., a gene, mRNAtranscript, or protein) enables parallel screening of the variants inorder to identify therapeutic candidates (e.g., small moleculecompounds, antibodies, antisense or RNAi nucleic acid compounds, etc.)that demonstrate efficacy across variants (Rothberg, Nat Biotechnol 2001March; 19(3):209-11). Such therapeutic candidates would be expected toshow equal efficacy across a larger segment of the patient population,thereby leading to a larger potential market for the therapeuticcandidate.

Furthermore, identifying variants of a potential therapeutic targetenables the most common form of the target to be used for selection oftherapeutic candidates, thereby helping to ensure that the experimentalactivity that is observed for the selected candidates reflects the realactivity expected in the largest proportion of a patient population(Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine,2002 March; S30-S36).

Additionally, screening therapeutic candidates against all knownvariants of a target can enable the early identification of potentialtoxicities and adverse reactions relating to particular variants. Forexample, variability in drug absorption, distribution, metabolism andexcretion (ADME) caused by, for example, SNPs in therapeutic targets ordrug metabolizing genes, can be identified, and this information can beutilized during the drug development process to minimize variability indrug disposition and develop therapeutic agents that are safer across awider range of a patient population. The SNPs of the present invention,including the variant proteins and encoding polymorphic nucleic acidmolecules provided in Tables 1-2, are useful in conjunction with avariety of toxicology methods established in the art, such as those setforth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (ornucleic acid molecules, either RNA or DNA) may cross-react with thevariant proteins (or polymorphic nucleic acid molecules) disclosed inTable 1, thereby significantly affecting the pharmacokinetic propertiesof the drug. Consequently, the protein variants and the SNP-containingnucleic acid molecules disclosed in Tables 1-2 are useful in developing,screening, and evaluating therapeutic agents that target correspondingart-known protein forms (or nucleic acid molecules). Additionally, asdiscussed above, knowledge of all polymorphic forms of a particular drugtarget enables the design of therapeutic agents that are effectiveagainst most or all such polymorphic forms of the drug target.

Pharmaceutical Compositions and Administration Thereof

Any of the VT-associated proteins, and encoding nucleic acid molecules,disclosed herein can be used as therapeutic targets (or directly usedthemselves as therapeutic compounds) for treating VT and relatedpathologies, and the present disclosure enables therapeutic compounds(e.g., small molecules, antibodies, therapeutic proteins, RNAi andantisense molecules, etc.) to be developed that target (or are comprisedof) any of these therapeutic targets.

In general, a therapeutic compound will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the therapeutic compound of this invention, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors.

Therapeutically effective amounts of therapeutic compounds may rangefrom, for example, approximately 0.01-50 mg per kilogram body weight ofthe recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as anexample, for administration to a 70 kg person, the dosage range wouldmost preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceuticalcompositions by any one of the following routes: oral, systemic (e.g.,transdermal, intranasal, or by suppository), or parenteral (e.g.,intramuscular, intravenous, or subcutaneous) administration. Thepreferred manner of administration is oral or parenteral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Oral compositions can take the form of tablets,pills, capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills, or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeuticcompound in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the therapeuticcompound. Such excipients may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 18^(th) ed., 1990).

The amount of the therapeutic compound in a formulation can vary withinthe full range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of the therapeutic compound based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about 1-80wt %.

Therapeutic compounds can be administered alone or in combination withother therapeutic compounds or in combination with one or more otheractive ingredient(s). For example, an inhibitor or stimulator of anVT-associated protein can be administered in combination with anotheragent that inhibits or stimulates the activity of the same or adifferent VT-associated protein to thereby counteract the affects of VT.

For further information regarding pharmacology, see Current Protocols inPharmacology, John Wiley & Sons, Inc., N.Y.

Human Identification Applications

In addition to their diagnostic and therapeutic uses in VT and relatedpathologies, the SNPs provided by the present invention are also usefulas human identification markers for such applications as forensics,paternity testing, and biometrics (see, e.g., Gill, “An assessment ofthe utility of single nucleotide polymorphisms (SNPs) for forensicpurposes”, Int J Legal Med. 2001; 114(4-5):204-10). Genetic variationsin the nucleic acid sequences between individuals can be used as geneticmarkers to identify individuals and to associate a biological samplewith an individual. Determination of which nucleotides occupy a set ofSNP positions in an individual identifies a set of SNP markers thatdistinguishes the individual. The more SNP positions that are analyzed,the lower the probability that the set of SNPs in one individual is thesame as that in an unrelated individual. Preferably, if multiple sitesare analyzed, the sites are unlinked (i.e., inherited independently).Thus, preferred sets of SNPs can be selected from among the SNPsdisclosed herein, which may include SNPs on different chromosomes, SNPson different chromosome arms, and/or SNPs that are dispersed oversubstantial distances along the same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use incertain forensic/human identification applications include SNPs locatedat degenerate codon positions (i.e., the third position in certaincodons which can be one of two or more alternative nucleotides and stillencode the same amino acid), since these SNPs do not affect the encodedprotein. SNPs that do not affect the encoded protein are expected to beunder less selective pressure and are therefore expected to be morepolymorphic in a population, which is typically an advantage forforensic/human identification applications. However, for certainforensics/human identification applications, such as predictingphenotypic characteristics (e.g., inferring ancestry or inferring one ormore physical characteristics of an individual) from a DNA sample, itmay be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1-2 (which are identified as“Applera” SNP source), Tables 1-2 provide SNP allele frequenciesobtained by re-sequencing the DNA of chromosomes from 39 individuals(Tables 1-2 also provide allele frequency information for “Celera”source SNPs and, where available, public SNPs from dbEST, HGBASE, and/orHGMD). The allele frequencies provided in Tables 1-2 enable these SNPsto be readily used for human identification applications. Although anySNP disclosed in Table 1 and/or Table 2 could be used for humanidentification, the closer that the frequency of the minor allele at aparticular SNP site is to 50%, the greater the ability of that SNP todiscriminate between different individuals in a population since itbecomes increasingly likely that two randomly selected individuals wouldhave different alleles at that SNP site. Using the SNP allelefrequencies provided in Tables 1-2, one of ordinary skill in the artcould readily select a subset of SNPs for which the frequency of theminor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%,40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables1-2 provide allele frequencies based on the re-sequencing of thechromosomes from 39 individuals, a subset of SNPs could readily beselected for human identification in which the total allele count of theminor allele at a particular SNP site is, for example, at least 1, 2, 4,8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other numberin-between.

Furthermore, Tables 1-2 also provide population group (interchangeablyreferred to herein as ethnic or racial groups) information coupled withthe extensive allele frequency information. For example, the group of 39individuals whose DNA was re-sequenced was made-up of 20 Caucasians and19 African-Americans. This population group information enables furtherrefinement of SNP selection for human identification. For example,preferred SNPs for human identification can be selected from Tables 1-2that have similar allele frequencies in both the Caucasian andAfrican-American populations; thus, for example, SNPs can be selectedthat have equally high discriminatory power in both populations.Alternatively, SNPs can be selected for which there is a statisticallysignificant difference in allele frequencies between the Caucasian andAfrican-American populations (as an extreme example, a particular allelemay be observed only in either the Caucasian or the African-Americanpopulation group but not observed in the other population group); suchSNPs are useful, for example, for predicting the race/ethnicity of anunknown perpetrator from a biological sample such as a hair or bloodstain recovered at a crime scene. For a discussion of using SNPs topredict ancestry from a DNA sample, including statistical methods, seeFrudakis et al., “A Classifier for the SNP-Based Inference of Ancestry,”Journal of Forensic Sciences 2003; 48(4):771-782.

SNPs have numerous advantages over other types of polymorphic markers,such as short tandem repeats (STRs). For example, SNPs can be easilyscored and are amenable to automation, making SNPs the markers of choicefor large-scale forensic databases. SNPs are found in much greaterabundance throughout the genome than repeat polymorphisms. Populationfrequencies of two polymorphic forms can usually be determined withgreater accuracy than those of multiple polymorphic forms atmulti-allelic loci. SNPs are mutationaly more stable than repeatpolymorphisms. SNPs are not susceptible to artifacts such as stutterbands that can hinder analysis. Stutter bands are frequently encounteredwhen analyzing repeat polymorphisms, and are particularly troublesomewhen analyzing samples such as crime scene samples that may containmixtures of DNA from multiple sources. Another significant advantage ofSNP markers over STR markers is the much shorter length of nucleic acidneeded to score a SNP. For example, STR markers are generally severalhundred base pairs in length. A SNP, on the other hand, comprises asingle nucleotide, and generally a short conserved region on either sideof the SNP position for primer and/or probe binding. This makes SNPsmore amenable to typing in highly degraded or aged biological samplesthat are frequently encountered in forensic casework in which DNA may befragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” allelesfrequently encountered when analyzing STR loci. Microvariants aredeletions or insertions within a repeat unit that change the size of theamplified DNA product so that the amplified product does not migrate atthe same rate as reference alleles with normal sized repeat units. Whenseparated by size, such as by electrophoresis on a polyacrylamide gel,microvariants do not align with a reference allelic ladder of standardsized repeat units, but rather migrate between the reference alleles.The reference allelic ladder is used for precise sizing of alleles forallele classification; therefore alleles that do not align with thereference allelic ladder lead to substantial analysis problems.Furthermore, when analyzing multi-allelic repeat polymorphisms,occasionally an allele is found that consists of more or less repeatunits than has been previously seen in the population, or more or lessrepeat alleles than are included in a reference allelic ladder. Thesealleles will migrate outside the size range of known alleles in areference allelic ladder, and therefore are referred to as “off-ladder”alleles. In extreme cases, the allele may contain so few or so manyrepeats that it migrates well out of the range of the reference allelicladder. In this situation, the allele may not even be observed, or, withmultiplex analysis, it may migrate within or close to the size range foranother locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder allelesencountered in STR analysis. Importantly, microvariants and off-ladderalleles may provide significant problems, and may be completely missed,when using analysis methods such as oligonucleotide hybridizationarrays, which utilize oligonucleotide probes specific for certain knownalleles. Furthermore, off-ladder alleles and microvariants encounteredwith STR analysis, even when correctly typed, may lead to improperstatistical analysis, since their frequencies in the population aregenerally unknown or poorly characterized, and therefore the statisticalsignificance of a matching genotype may be questionable. All theseadvantages of SNP analysis are considerable in light of the consequencesof most DNA identification cases, which may lead to life imprisonmentfor an individual, or re-association of remains to the family of adeceased individual.

DNA can be isolated from biological samples such as blood, bone, hair,saliva, or semen, and compared with the DNA from a reference source atparticular SNP positions. Multiple SNP markers can be assayedsimultaneously in order to increase the power of discrimination and thestatistical significance of a matching genotype. For example,oligonucleotide arrays can be used to genotype a large number of SNPssimultaneously. The SNPs provided by the present invention can beassayed in combination with other polymorphic genetic markers, such asother SNPs known in the art or STRs, in order to identify an individualor to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotypedfor inclusion in a database of DNA genotypes, for example, a criminalDNA databank such as the FBI's Combined DNA Index System (CODIS)database. A genotype obtained from a biological sample of unknown sourcecan then be queried against the database to find a matching genotype,with the SNPs of the present invention providing nucleotide positions atwhich to compare the known and unknown DNA sequences for identity.Accordingly, the present invention provides a database comprising novelSNPs or SNP alleles of the present invention (e.g., the database cancomprise information indicating which alleles are possessed byindividual members of a population at one or more novel SNP sites of thepresent invention), such as for use in forensics, biometrics, or otherhuman identification applications. Such a database typically comprises acomputer-based system in which the SNPs or SNP alleles of the presentinvention are recorded on a computer readable medium (see the section ofthe present specification entitled “Computer-Related Embodiments”).

The SNPs of the present invention can also be assayed for use inpaternity testing. The object of paternity testing is usually todetermine whether a male is the father of a child. In most cases, themother of the child is known and thus, the mother's contribution to thechild's genotype can be traced. Paternity testing investigates whetherthe part of the child's genotype not attributable to the mother isconsistent with that of the putative father. Paternity testing can beperformed by analyzing sets of polymorphisms in the putative father andthe child, with the SNPs of the present invention providing nucleotidepositions at which to compare the putative father's and child's DNAsequences for identity. If the set of polymorphisms in the childattributable to the father does not match the set of polymorphisms ofthe putative father, it can be concluded, barring experimental error,that the putative father is not the father of the child. If the set ofpolymorphisms in the child attributable to the father match the set ofpolymorphisms of the putative father, a statistical calculation can beperformed to determine the probability of coincidental match, and aconclusion drawn as to the likelihood that the putative father is thetrue biological father of the child.

In addition to paternity testing, SNPs are also useful for other typesof kinship testing, such as for verifying familial relationships forimmigration purposes, or for cases in which an individual alleges to berelated to a deceased individual in order to claim an inheritance fromthe deceased individual, etc. For further information regarding theutility of SNPs for paternity testing and other types of kinshiptesting, including methods for statistical analysis, see Krawczak,“Informativity assessment for biallelic single nucleotidepolymorphisms”, Electrophoresis 1999 June; 20(8):1676-81.

The use of the SNPs of the present invention for human identificationfurther extends to various authentication systems, commonly referred toas biometric systems, which typically convert physical characteristicsof humans (or other organisms) into digital data. Biometric systemsinclude various technological devices that measure such uniqueanatomical or physiological characteristics as finger, thumb, or palmprints; hand geometry; vein patterning on the back of the hand; bloodvessel patterning of the retina and color and texture of the iris;facial characteristics; voice patterns; signature and typing dynamics;and DNA. Such physiological measurements can be used to verify identityand, for example, restrict or allow access based on the identification.Examples of applications for biometrics include physical area security,computer and network security, aircraft passenger check-in and boarding,financial transactions, medical records access, government benefitdistribution, voting, law enforcement, passports, visas and immigration,prisons, various military applications, and for restricting access toexpensive or dangerous items, such as automobiles or guns (see, forexample, O'Connor, Stanford Technology Law Review and U.S. Pat. No.6,119,096).

Groups of SNPs, particularly the SNPs provided by the present invention,can be typed to uniquely identify an individual for biometricapplications such as those described above. Such SNP typing can readilybe accomplished using, for example, DNA chips/arrays. Preferably, aminimally invasive means for obtaining a DNA sample is utilized. Forexample, PCR amplification enables sufficient quantities of DNA foranalysis to be obtained from buccal swabs or fingerprints, which containDNA-containing skin cells and oils that are naturally transferred duringcontact.

Further information regarding techniques for using SNPs inforensic/human identification applications can be found in, for example,Current Protocols in Human Genetics, John Wiley & Sons, N.Y. (2002),14.1-14.7.

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules,many of which encode proteins having variant amino acid sequences ascompared to the art-known (i.e., wild-type) proteins. Amino acidsequences encoded by the polymorphic nucleic acid molecules of thepresent invention are referred to as SEQ ID NOS: 126-250 in Table 1 andprovided in the Sequence Listing. These variants will generally bereferred to herein as variant proteins/peptides/polypeptides, orpolymorphic proteins/peptides/polypeptides of the present invention. Theterms “protein,” “peptide,” and “polypeptide” are used hereininterchangeably.

A variant protein of the present invention may be encoded by, forexample, a nonsynonymous nucleotide substitution at any one of the cSNPpositions disclosed herein. In addition, variant proteins may alsoinclude proteins whose expression, structure, and/or function is alteredby a SNP disclosed herein, such as a SNP that creates or destroys a stopcodon, a SNP that affects splicing, and a SNP in control/regulatoryelements, e.g. promoters, enhancers, or transcription factor bindingdomains.

As used herein, a protein or peptide is said to be “isolated” or“purified” when it is substantially free of cellular material orchemical precursors or other chemicals. The variant proteins of thepresent invention can be purified to homogeneity or other lower degreesof purity. The level of purification will be based on the intended use.The key feature is that the preparation allows for the desired functionof the variant protein, even if in the presence of considerable amountsof other components.

As used herein, “substantially free of cellular material” includespreparations of the variant protein having less than about 30% (by dryweight) other proteins (i.e., contaminating protein), less than about20% other proteins, less than about 10% other proteins, or less thanabout 5% other proteins. When the variant protein is recombinantlyproduced, it can also be substantially free of culture medium, i.e.,culture medium represents less than about 20% of the volume of theprotein preparation.

The language “substantially free of chemical precursors or otherchemicals” includes preparations of the variant protein in which it isseparated from chemical precursors or other chemicals that are involvedin its synthesis. In one embodiment, the language “substantially free ofchemical precursors or other chemicals” includes preparations of thevariant protein having less than about 30% (by dry weight) chemicalprecursors or other chemicals, less than about 20% chemical precursorsor other chemicals, less than about 10% chemical precursors or otherchemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturallyexpress it, purified from cells that have been altered to express it(recombinant host cells), or synthesized using known protein synthesismethods. For example, a nucleic acid molecule containing SNP(s) encodingthe variant protein can be cloned into an expression vector, theexpression vector introduced into a host cell, and the variant proteinexpressed in the host cell. The variant protein can then be isolatedfrom the cells by any appropriate purification scheme using standardprotein purification techniques. Examples of these techniques aredescribed in detail below (Sambrook and Russell, 2000, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.).

The present invention provides isolated variant proteins that comprise,consist of or consist essentially of amino acid sequences that containone or more variant amino acids encoded by one or more codons thatcontain a SNP of the present invention.

Accordingly, the present invention provides variant proteins thatconsist of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists of an amino acid sequencewhen the amino acid sequence is the entire amino acid sequence of theprotein.

The present invention further provides variant proteins that consistessentially of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists essentially of an aminoacid sequence when such an amino acid sequence is present with only afew additional amino acid residues in the final protein.

The present invention further provides variant proteins that compriseamino acid sequences that contain one or more amino acid polymorphisms(or truncations or extensions due to creation or destruction of a stopcodon, respectively) encoded by the SNPs provided in Table 1 and/orTable 2. A protein comprises an amino acid sequence when the amino acidsequence is at least part of the final amino acid sequence of theprotein. In such a fashion, the protein may contain only the variantamino acid sequence or have additional amino acid residues, such as acontiguous encoded sequence that is naturally associated with it orheterologous amino acid residues. Such a protein can have a fewadditional amino acid residues or can comprise many more additionalamino acids. A brief description of how various types of these proteinscan be made and isolated is provided below.

The variant proteins of the present invention can be attached toheterologous sequences to form chimeric or fusion proteins. Suchchimeric and fusion proteins comprise a variant protein operativelylinked to a heterologous protein having an amino acid sequence notsubstantially homologous to the variant protein. “Operatively linked”indicates that the coding sequences for the variant protein and theheterologous protein are ligated in-frame. The heterologous protein canbe fused to the N-terminus or C-terminus of the variant protein. Inanother embodiment, the fusion protein is encoded by a fusionpolynucleotide that is synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers which give rise tocomplementary overhangs between two consecutive gene fragments which cansubsequently be annealed and re-amplified to generate a chimeric genesequence (see Ausubel et al., Current Protocols in Molecular Biology,1992). Moreover, many expression vectors are commercially available thatalready encode a fusion moiety (e.g., a GST protein). A variantprotein-encoding nucleic acid can be cloned into such an expressionvector such that the fusion moiety is linked in-frame to the variantprotein.

In many uses, the fusion protein does not affect the activity of thevariant protein. The fusion protein can include, but is not limited to,enzymatic fusion proteins, for example, beta-galactosidase fusions,yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-taggedand Ig fusions. Such fusion proteins, particularly poly-His fusions, canfacilitate their purification following recombinant expression. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of a protein can be increased by using a heterologous signalsequence. Fusion proteins are further described in, for example, Terpe,“Overview of tag protein fusions: from molecular and biochemicalfundamentals to commercial systems”, Appl Microbiol Biotechnol. 2003January; 60(5):523-33. Epub 2002 Nov. 7; Graddis et al., “Designingproteins that work using recombinant technologies”, Curr PharmBiotechnol. 2002 December; 3(4):285-97; and Nilsson et al., “Affinityfusion strategies for detection, purification, and immobilization ofrecombinant proteins”, Protein Expr Purif. 1997 October; 11 (1): 1-16.

The present invention also relates to further obvious variants of thevariant polypeptides of the present invention, such asnaturally-occurring mature forms (e.g., alleleic variants),non-naturally occurring recombinantly-derived variants, and orthologsand paralogs of such proteins that share sequence homology. Suchvariants can readily be generated using art-known techniques in thefields of recombinant nucleic acid technology and protein biochemistry.It is understood, however, that variants exclude those known in theprior art before the present invention.

Further variants of the variant polypeptides disclosed in Table 1 cancomprise an amino acid sequence that shares at least 70-80%, 80-85%,85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identitywith an amino acid sequence disclosed in Table 1 (or a fragment thereof)and that includes a novel amino acid residue (allele) disclosed in Table1 (which is encoded by a novel SNP allele). Thus, an aspect of thepresent invention that is specifically contemplated are polypeptidesthat have a certain degree of sequence variation compared with thepolypeptide sequences shown in Table 1, but that contain a novel aminoacid residue (allele) encoded by a novel SNP allele disclosed herein. Inother words, as long as a polypeptide contains a novel amino acidresidue disclosed herein, other portions of the polypeptide that flankthe novel amino acid residue can vary to some degree from thepolypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, ofproteins that comprise one of the amino acid sequences disclosed hereincan readily be identified as having complete sequence identity to one ofthe variant proteins of the present invention as well as being encodedby the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having somedegree of significant sequence homology/identity to at least a portionof a variant peptide as well as being encoded by a gene from anotherorganism. Preferred orthologs will be isolated from non-human mammals,preferably primates, for the development of human therapeutic targetsand agents. Such orthologs can be encoded by a nucleic acid sequencethat hybridizes to a variant peptide-encoding nucleic acid moleculeunder moderate to stringent conditions depending on the degree ofrelatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containingdeletions, additions and substitutions in the amino acid sequence causedby the SNPs of the present invention. One class of substitutions isconserved amino acid substitutions in which a given amino acid in apolypeptide is substituted for another amino acid of likecharacteristics. Typical conservative substitutions are replacements,one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile;interchange of the hydroxyl residues Ser and Thr; exchange of the acidicresidues Asp and Glu; substitution between the amide residues Asn andGln; exchange of the basic residues Lys and Arg; and replacements amongthe aromatic residues Phe and Tyr. Guidance concerning which amino acidchanges are likely to be phenotypically silent are found in, forexample, Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one ormore activities, e.g. ability to bind another molecule, ability tocatalyze a substrate, ability to mediate signaling, etc. Fullyfunctional variants typically contain only conservative variations orvariations in non-critical residues or in non-critical regions.Functional variants can also contain substitution of similar amino acidsthat result in no change or an insignificant change in function.Alternatively, such substitutions may positively or negatively affectfunction to some degree. Non-functional variants typically contain oneor more non-conservative amino acid substitutions, deletions,insertions, inversions, truncations or extensions, or a substitution,insertion, inversion, or deletion of a critical residue or in a criticalregion.

Amino acids that are essential for function of a protein can beidentified by methods known in the art, such as site-directedmutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science244:1081-1085 (1989)), particularly using the amino acid sequence andpolymorphism information provided in Table 1. The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for biological activitysuch as enzyme activity or in assays such as an in vitro proliferativeactivity. Sites that are critical for binding partner/substrate bindingcan also be determined by structural analysis such as crystallization,nuclear magnetic resonance or photoaffinity labeling (Smith et al., J.Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312(1992)).

Polypeptides can contain amino acids other than the 20 amino acidscommonly referred to as the 20 naturally occurring amino acids. Further,many amino acids, including the terminal amino acids, may be modified bynatural processes, such as processing and other post-translationalmodifications, or by chemical modification techniques well known in theart. Accordingly, the variant proteins of the present invention alsoencompass derivatives or analogs in which a substituted amino acidresidue is not one encoded by the genetic code, in which a substituentgroup is included, in which the mature polypeptide is fused with anothercompound, such as a compound to increase the half-life of thepolypeptide (e.g., polyethylene glycol), or in which additional aminoacids are fused to the mature polypeptide, such as a leader or secretorysequence or a sequence for purification of the mature polypeptide or apro-protein sequence.

Known protein modifications include, but are not limited to,acetylation, acylation, ADP-ribosylation, amidation, covalent attachmentof flavin, covalent attachment of a heme moiety, covalent attachment ofa nucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphotidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Such protein modifications are well known to those of skill in the artand have been described in great detail in the scientific literature.Several particularly common modifications, glycosylation, lipidattachment, sulfation, gamma-carboxylation of glutamic acid residues,hydroxylation and ADP-ribosylation, for instance, are described in mostbasic texts, such as Proteins—Structure and Molecular Properties, 2ndEd., T. E. Creighton, W. H. Freeman and Company, New York (1993); Wold,F., Posttranslational Covalent Modification of Proteins, B. C. Johnson,Ed., Academic Press, New York 1-12 (1983); Seifter et al., Meth.Enzymol. 182: 626-646 (1990); and Rattan et al., Ann. N.Y. Acad. Sci.663:48-62 (1992).

The present invention further provides fragments of the variant proteinsin which the fragments contain one or more amino acid sequencevariations (e.g., substitutions, or truncations or extensions due tocreation or destruction of a stop codon) encoded by one or more SNPsdisclosed herein. The fragments to which the invention pertains,however, are not to be construed as encompassing fragments that havebeen disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14,16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or morecontiguous amino acid residues from a variant protein, wherein at leastone amino acid residue is affected by a SNP of the present invention,e.g., a variant amino acid residue encoded by a nonsynonymous nucleotidesubstitution at a cSNP position provided by the present invention. Thevariant amino acid encoded by a cSNP may occupy any residue positionalong the sequence of the fragment. Such fragments can be chosen basedon the ability to retain one or more of the biological activities of thevariant protein or the ability to perform a function, e.g., act as animmunogen. Particularly important fragments are biologically activefragments. Such fragments will typically comprise a domain or motif of avariant protein of the present invention, e.g., active site,transmembrane domain, or ligand/substrate binding domain. Otherfragments include, but are not limited to, domain or motif-containingfragments, soluble peptide fragments, and fragments containingimmunogenic structures. Predicted domains and functional sites arereadily identifiable by computer programs well known to those of skillin the art (e.g., PROSITE analysis) (Current Protocols in ProteinScience, John Wiley & Sons, N.Y. (2002)).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a varietyof ways, including but not limited to, in assays to determine thebiological activity of a variant protein, such as in a panel of multipleproteins for high-throughput screening; to raise antibodies or to elicitanother type of immune response; as a reagent (including the labeledreagent) in assays designed to quantitatively determine levels of thevariant protein (or its binding partner) in biological fluids; as amarker for cells or tissues in which it is preferentially expressed(either constitutively or at a particular stage of tissuedifferentiation or development or in a disease state); as a target forscreening for a therapeutic agent; and as a direct therapeutic agent tobe administered into a human subject. Any of the variant proteinsdisclosed herein may be developed into reagent grade or kit format forcommercialization as research products. Methods for performing the useslisted above are well known to those skilled in the art (see, e.g.,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor LaboratoryPress, Sambrook and Russell, 2000, and Methods in Enzymology: Guide toMolecular Cloning Techniques, Academic Press, Berger, S. L. and A. R.Kimmel eds., 1987).

In a specific embodiment of the invention, the methods of the presentinvention include detection of one or more variant proteins disclosedherein. Variant proteins are disclosed in Table 1 and in the SequenceListing as SEQ ID NOS: 126-250. Detection of such proteins can beaccomplished using, for example, antibodies, small molecule compounds,aptamers, ligands/substrates, other proteins or protein fragments, orother protein-binding agents. Preferably, protein detection agents arespecific for a variant protein of the present invention and cantherefore discriminate between a variant protein of the presentinvention and the wild-type protein or another variant form. This cangenerally be accomplished by, for example, selecting or designingdetection agents that bind to the region of a protein that differsbetween the variant and wild-type protein, such as a region of a proteinthat contains one or more amino acid substitutions that is/are encodedby a non-synonymous cSNP of the present invention, or a region of aprotein that follows a nonsense mutation-type SNP that creates a stopcodon thereby leading to a shorter polypeptide, or a region of a proteinthat follows a read-through mutation-type SNP that destroys a stop codonthereby leading to a longer polypeptide in which a portion of thepolypeptide is present in one version of the polypeptide but not theother.

In another specific aspect of the invention, the variant proteins of thepresent invention are used as targets for diagnosing VT or fordetermining predisposition to VT in a human. Accordingly, the inventionprovides methods for detecting the presence of, or levels of, one ormore variant proteins of the present invention in a cell, tissue, ororganism. Such methods typically involve contacting a test sample withan agent (e.g., an antibody, small molecule compound, or peptide)capable of interacting with the variant protein such that specificbinding of the agent to the variant protein can be detected. Such anassay can be provided in a single detection format or a multi-detectionformat such as an array, for example, an antibody or aptamer array(arrays for protein detection may also be referred to as “proteinchips”). The variant protein of interest can be isolated from a testsample and assayed for the presence of a variant amino acid sequenceencoded by one or more SNPs disclosed by the present invention. The SNPsmay cause changes to the protein and the corresponding proteinfunction/activity, such as through non-synonymous substitutions inprotein coding regions that can lead to amino acid substitutions,deletions, insertions, and/or rearrangements; formation or destructionof stop codons; or alteration of control elements such as promoters.SNPs may also cause inappropriate post-translational modifications.

One preferred agent for detecting a variant protein in a sample is anantibody capable of selectively binding to a variant form of the protein(antibodies are described in greater detail in the next section). Suchsamples include, for example, tissues, cells, and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject.

In vitro methods for detection of the variant proteins associated withVT that are disclosed herein and fragments thereof include, but are notlimited to, enzyme linked immunosorbent assays (ELISAs),radioimmunoassays (RIA), Western blots, immunoprecipitations,immunofluorescence, and protein arrays/chips (e.g., arrays of antibodiesor aptamers). For further information regarding immunoassays and relatedprotein detection methods, see Current Protocols in Immunology, JohnWiley & Sons, N.Y., and Hage, “Immunoassays”, Anal Chem. 1999 Jun. 15;71(12):294R-304R.

Additional analytic methods of detecting amino acid variants include,but are not limited to, altered electrophoretic mobility, alteredtryptic peptide digest, altered protein activity in cell-based orcell-free assay, alteration in ligand or antibody-binding pattern,altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject byintroducing into the subject a labeled antibody (or other type ofdetection reagent) specific for a variant protein. For example, theantibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based onthe class or action of the protein. For example, proteins isolated fromhumans and their mammalian orthologs serve as targets for identifyingagents (e.g., small molecule drugs or antibodies) for use in therapeuticapplications, particularly for modulating a biological or pathologicalresponse in a cell or tissue that expresses the protein. Pharmaceuticalagents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compoundscan be developed that modulate protein function. For example, many SNPsdisclosed herein affect the amino acid sequence of the encoded protein(e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Suchalterations in the encoded amino acid sequence may affect proteinfunction, particularly if such amino acid sequence variations occur infunctional protein domains, such as catalytic domains, ATP-bindingdomains, or ligand/substrate binding domains. It is well established inthe art that variant proteins having amino acid sequence variations infunctional domains can cause or influence pathological conditions. Insuch instances, compounds (e.g., small molecule drugs or antibodies) canbe developed that target the variant protein and modulate (e.g., up- ordown-regulate) protein function/activity.

The therapeutic methods of the present invention further include methodsthat target one or more variant proteins of the present invention.Variant proteins can be targeted using, for example, small moleculecompounds, antibodies, aptamers, ligands/substrates, other proteins, orother protein-binding agents. Additionally, the skilled artisan willrecognize that the novel protein variants (and polymorphic nucleic acidmolecules) disclosed in Table 1 may themselves be directly used astherapeutic agents by acting as competitive inhibitors of correspondingart-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful indrug screening assays, in cell-based or cell-free systems. Cell-basedsystems can utilize cells that naturally express the protein, a biopsyspecimen, or cell cultures. In one embodiment, cell-based assays involverecombinant host cells expressing the variant protein. Cell-free assayscan be used to detect the ability of a compound to directly bind to avariant protein or to the corresponding SNP-containing nucleic acidfragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriatefragments thereof, can be used in high-throughput screening assays totest candidate compounds for the ability to bind and/or modulate theactivity of the variant protein. These candidate compounds can befurther screened against a protein having normal function (e.g., awild-type/non-variant protein) to further determine the effect of thecompound on the protein activity. Furthermore, these compounds can betested in animal or invertebrate systems to determine in vivoactivity/effectiveness. Compounds can be identified that activate(agonists) or inactivate (antagonists) the variant protein, anddifferent compounds can be identified that cause various degrees ofactivation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for theability to stimulate or inhibit interaction between the variant proteinand a target molecule that normally interacts with the protein. Thetarget can be a ligand, a substrate or a binding partner that theprotein normally interacts with (for example, epinephrine ornorepinephrine). Such assays typically include the steps of combiningthe variant protein with a candidate compound under conditions thatallow the variant protein, or fragment thereof, to interact with thetarget molecule, and to detect the formation of a complex between theprotein and the target or to detect the biochemical consequence of theinteraction with the variant protein and the target, such as any of theassociated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as solublepeptides, including Ig-tailed fusion peptides and members of randompeptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991);Houghten et al., Nature 354:84-86 (1991)) and combinatorialchemistry-derived molecular libraries made of D- and/or L-configurationamino acids; 2) phosphopeptides (e.g., members of random and partiallydegenerate, directed phosphopeptide libraries, see, e.g., Songyang etal., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal,monoclonal, humanized, anti-idiotypic, chimeric, and single chainantibodies as well as Fab, F(ab′)₂, Fab expression library fragments,and epitope-binding fragments of antibodies); and 4) small organic andinorganic molecules (e.g., molecules obtained from combinatorial andnatural product libraries).

One candidate compound is a soluble fragment of the variant protein thatcompetes for ligand binding. Other candidate compounds include mutantproteins or appropriate fragments containing mutations that affectvariant protein function and thus compete for ligand. Accordingly, afragment that competes for ligand, for example with a higher affinity,or a fragment that binds ligand but does not allow release, isencompassed by the invention.

The invention further includes other end point assays to identifycompounds that modulate (stimulate or inhibit) variant protein activity.The assays typically involve an assay of events in the signaltransduction pathway that indicate protein activity. Thus, theexpression of genes that are up or down-regulated in response to thevariant protein dependent signal cascade can be assayed. In oneembodiment, the regulatory region of such genes can be operably linkedto a marker that is easily detectable, such as luciferase.Alternatively, phosphorylation of the variant protein, or a variantprotein target, could also be measured. Any of the biological orbiochemical functions mediated by the variant protein can be used as anendpoint assay. These include all of the biochemical or biologicalevents described herein, in the references cited herein, incorporated byreference for these endpoint assay targets, and other functions known tothose of ordinary skill in the art.

Binding and/or activating compounds can also be screened by usingchimeric variant proteins in which an amino terminal extracellulardomain or parts thereof, an entire transmembrane domain or subregions,and/or the carboxyl terminal intracellular domain or parts thereof, canbe replaced by heterologous domains or subregions. For example, asubstrate-binding region can be used that interacts with a differentsubstrate than that which is normally recognized by a variant protein.Accordingly, a different set of signal transduction components isavailable as an end-point assay for activation. This allows for assaysto be performed in other than the specific host cell from which thevariant protein is derived.

The variant proteins are also useful in competition binding assays inmethods designed to discover compounds that interact with the variantprotein. Thus, a compound can be exposed to a variant protein underconditions that allow the compound to bind or to otherwise interact withthe variant protein. A binding partner, such as ligand, that normallyinteracts with the variant protein is also added to the mixture. If thetest compound interacts with the variant protein or its binding partner,it decreases the amount of complex formed or activity from the variantprotein. This type of assay is particularly useful in screening forcompounds that interact with specific regions of the variant protein(Hodgson, Bio/technology, 1992, Sep. 10(9), 973-80).

To perform cell-free drug screening assays, it is sometimes desirable toimmobilize either the variant protein or a fragment thereof, or itstarget molecule, to facilitate separation of complexes from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Any method for immobilizing proteins onmatrices can be used in drug screening assays. In one embodiment, afusion protein containing an added domain allows the protein to be boundto a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteinscan be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.Louis, Mo.) or glutathione derivatized microtitre plates, which are thencombined with the cell lysates (e.g., ³⁵S-labeled) and a candidatecompound, such as a drug candidate, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads can bewashed to remove any unbound label, and the matrix immobilized andradiolabel determined directly, or in the supernatant after thecomplexes are dissociated. Alternatively, the complexes can bedissociated from the matrix, separated by SDS-PAGE, and the level ofbound material found in the bead fraction quantitated from the gel usingstandard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilizedutilizing conjugation of biotin and streptavidin. Alternatively,antibodies reactive with the variant protein but which do not interferewith binding of the variant protein to its target molecule can bederivatized to the wells of the plate, and the variant protein trappedin the wells by antibody conjugation. Preparations of the targetmolecule and a candidate compound are incubated in the variantprotein-presenting wells and the amount of complex trapped in the wellcan be quantitated. Methods for detecting such complexes, in addition tothose described above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with the proteintarget molecule, or which are reactive with variant protein and competewith the target molecule, and enzyme-linked assays that rely ondetecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to thesedrug screening assays can be used to treat a subject with a disordermediated by the protein pathway, such as VT. These methods of treatmenttypically include the steps of administering the modulators of proteinactivity in a pharmaceutical composition to a subject in need of suchtreatment.

The variant proteins, or fragments thereof, disclosed herein canthemselves be directly used to treat a disorder characterized by anabsence of, inappropriate, or unwanted expression or activity of thevariant protein. Accordingly, methods for treatment include the use of avariant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as“bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g.,U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura etal. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993)Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696;and Brent WO94/10300) to identify other proteins that bind to orinteract with the variant protein and are involved in variant proteinactivity. Such variant protein-binding proteins are also likely to beinvolved in the propagation of signals by the variant proteins orvariant protein targets as, for example, elements of a protein-mediatedsignaling pathway. Alternatively, such variant protein-binding proteinsare inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of mosttranscription factors, which typically consist of separable DNA-bindingand activation domains. Briefly, the assay typically utilizes twodifferent DNA constructs. In one construct, the gene that codes for avariant protein is fused to a gene encoding the DNA binding domain of aknown transcription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. If the “bait” andthe “prey” proteins are able to interact, in vivo, forming a variantprotein-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., LacZ) that is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detected,and cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene that encodes the proteinthat interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind tothe variant proteins disclosed herein and fragments thereof. Suchantibodies may be used to quantitatively or qualitatively detect thevariant proteins of the present invention. As used herein, an antibodyselectively binds a target variant protein when it binds the variantprotein and does not significantly bind to non-variant proteins, i.e.,the antibody does not significantly bind to normal, wild-type, orart-known proteins that do not contain a variant amino acid sequence dueto one or more SNPs of the present invention (variant amino acidsequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPsthat create a stop codon, thereby causing a truncation of a polypeptideor SNPs that cause read-through mutations resulting in an extension of apolypeptide).

As used herein, an antibody is defined in terms consistent with thatrecognized in the art: they are multi-subunit proteins produced by anorganism in response to an antigen challenge. The antibodies of thepresent invention include both monoclonal antibodies and polyclonalantibodies, as well as antigen-reactive proteolytic fragments of suchantibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, anantibody of the present invention further includes any of a variety ofengineered antigen-binding molecules such as a chimeric antibody (U.S.Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc. Natl. Acad.Sci. USA, 81:6851, 1984; Neuberger et al., Nature 312:604, 1984), ahumanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089; and 5,565,332),a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544,1989), a bispecific antibody with two binding specificities (Segal etal., J. Immunol. Methods 248:1, 2001; Carter, J. Immunol. Methods 248:7,2001), a diabody, a triabody, and a tetrabody (Todorovska et al., J.Immunol. Methods, 248:47, 2001), as well as a Fab conjugate (dimer ortrimer), and a minibody.

Many methods are known in the art for generating and/or identifyingantibodies to a given target antigen (Harlow, Antibodies, Cold SpringHarbor Press, (1989)). In general, an isolated peptide (e.g., a variantprotein of the present invention) is used as an immunogen and isadministered to a mammalian organism, such as a rat, rabbit, hamster ormouse. Either a full-length protein, an antigenic peptide fragment(e.g., a peptide fragment containing a region that varies between avariant protein and a corresponding wild-type protein), or a fusionprotein can be used. A protein used as an immunogen may benaturally-occurring, synthetic or recombinantly produced, and may beadministered in combination with an adjuvant, including but not limitedto, Freund's (complete and incomplete), mineral gels such as aluminumhydroxide, surface active substance such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin,dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology (Kohlerand Milstein, Nature, 256:495, 1975), which immortalizes cells secretinga specific monoclonal antibody. The immortalized cell lines can becreated in vitro by fusing two different cell types, typicallylymphocytes, and tumor cells. The hybridoma cells may be cultivated invitro or in vivo. Additionally, fully human antibodies can be generatedby transgenic animals (He et al., J. Immunol., 169:595, 2002). Fd phageand Fd phagemid technologies may be used to generate and selectrecombinant antibodies in vitro (Hoogenboom and Chames, Immunol. Today21:371, 2000; Liu et al., J. Mol. Biol. 315:1063, 2002). Thecomplementarity-determining regions of an antibody can be identified,and synthetic peptides corresponding to such regions may be used tomediate antigen binding (U.S. Pat. No. 5,637,677).

Antibodies are preferably prepared against regions or discrete fragmentsof a variant protein containing a variant amino acid sequence ascompared to the corresponding wild-type protein (e.g., a region of avariant protein that includes an amino acid encoded by a nonsynonymouscSNP, a region affected by truncation caused by a nonsense SNP thatcreates a stop codon, or a region resulting from the destruction of astop codon due to read-through mutation caused by a SNP). Furthermore,preferred regions will include those involved in function/activityand/or protein/binding partner interaction. Such fragments can beselected on a physical property, such as fragments corresponding toregions that are located on the surface of the protein, e.g.,hydrophilic regions, or can be selected based on sequence uniqueness, orbased on the position of the variant amino acid residue(s) encoded bythe SNPs provided by the present invention. An antigenic fragment willtypically comprise at least about 8-10 contiguous amino acid residues inwhich at least one of the amino acid residues is an amino acid affectedby a SNP disclosed herein. The antigenic peptide can comprise, however,at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) ormore amino acid residues, provided that at least one amino acid isaffected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated bycoupling (i.e., physically linking) the antibody or an antigen-reactivefragment thereof to a detectable substance. Detectable substancesinclude, but are not limited to, various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, β-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents,are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,”Expert Rev Vaccines. 2003 February; 2(1):53-9; Ross et al., “Anticancerantibodies,” Am J Clin Pathol. 2003 April; 119(4):472-85; Goldenberg,“Advancing role of radiolabeled antibodies in the therapy of cancer,”Cancer Immunol Immunother. 2003 May; 52(5):281-96. Epub 2003 Mar. 11;Ross et al., “Antibody-based therapeutics in oncology,” Expert RevAnticancer Ther. 2003 February; 3(1): 107-21; Cao et al., “Bispecificantibody conjugates in therapeutics,” Adv Drug Deliv Rev. 2003 Feb. 10;55(2):171-97; von Mehren et al., “Monoclonal antibody therapy forcancer,” Annu Rev Med. 2003; 54:343-69. Epub 2001 Dec. 3; Hudson et al.,“Engineered antibodies,” Nat Med. 2003 January; 9(1):129-34; Brekke etal., “Therapeutic antibodies for human diseases at the dawn of thetwenty-first century,” Nat Rev Drug Discov. 2003 January; 2(1):52-62(Erratum in: Nat Rev Drug Discov. 2003 March; 2(3):240); Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol. 2002 December; 13(6):625-9; Andreakos etal., “Monoclonal antibodies in immune and inflammatory diseases,” CurrOpin Biotechnol. 2002 December; 13(6):615-20; Kellermann et al.,“Antibody discovery: the use of transgenic mice to generate humanmonoclonal antibodies for therapeutics,” Curr Opin Biotechnol. 2002December; 13(6):593-7; Pini et al., “Phage display and colony filterscreening for high-throughput selection of antibody libraries,” CombChem High Throughput Screen. 2002 November; 5(7):503-10; Batra et al.,“Pharmacokinetics and biodistribution of genetically engineeredantibodies,” Curr Opin Biotechnol. 2002 December; 13(6):603-8; andTangri et al., “Rationally engineered proteins or antibodies with absentor reduced immunogenicity,” Curr Med Chem. 2002 December; 9(24):2191-9.

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the presentinvention from a natural cell source or from recombinant host cells bystandard techniques, such as affinity chromatography orimmunoprecipitation. In addition, antibodies are useful for detectingthe presence of a variant protein of the present invention in cells ortissues to determine the pattern of expression of the variant proteinamong various tissues in an organism and over the course of normaldevelopment or disease progression. Further, antibodies can be used todetect variant protein in situ, in vitro, in a bodily fluid, or in acell lysate or supernatant in order to evaluate the amount and patternof expression. Also, antibodies can be used to assess abnormal tissuedistribution, abnormal expression during development, or expression inan abnormal condition, such as VT. Additionally, antibody detection ofcirculating fragments of the full-length variant protein can be used toidentify turnover.

Antibodies to the variant proteins of the present invention are alsouseful in pharmacogenomic analysis. Thus, antibodies against variantproteins encoded by alternative SNP alleles can be used to identifyindividuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variantprotein in disease states such as in active stages of the disease or inan individual with a predisposition to a disease related to theprotein's function, particularly VT. Antibodies specific for a variantprotein encoded by a SNP-containing nucleic acid molecule of the presentinvention can be used to assay for the presence of the variant protein,such as to screen for predisposition to VT as indicated by the presenceof the variant protein.

Antibodies are also useful as diagnostic tools for evaluating thevariant proteins in conjunction with analysis by electrophoreticmobility, isoelectric point, tryptic peptide digest, and other physicalassays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specificvariant protein has been correlated with expression in a specifictissue, antibodies that are specific for this protein can be used toidentify a tissue type.

Antibodies can also be used to assess aberrant subcellular localizationof a variant protein in cells in various tissues. The diagnostic usescan be applied, not only in genetic testing, but also in monitoring atreatment modality. Accordingly, where treatment is ultimately aimed atcorrecting the expression level or the presence of variant protein oraberrant tissue distribution or developmental expression of a variantprotein, antibodies directed against the variant protein or relevantfragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function,for example, by blocking the binding of a variant protein to a bindingpartner. These uses can also be applied in a therapeutic context inwhich treatment involves inhibiting a variant protein's function. Anantibody can be used, for example, to block or competitively inhibitbinding, thus modulating (agonizing or antagonizing) the activity of avariant protein. Antibodies can be prepared against specific variantprotein fragments containing sites required for function or against anintact variant protein that is associated with a cell or cell membrane.For in vivo administration, an antibody may be linked with an additionaltherapeutic payload such as a radionuclide, an enzyme, an immunogenicepitope, or a cytotoxic agent. Suitable cytotoxic agents include, butare not limited to, bacterial toxin such as diphtheria, and plant toxinsuch as ricin. The in vivo half-life of an antibody or a fragmentthereof may be lengthened by pegylation through conjugation topolyethylene glycol (Leong et al., Cytokine 16:106, 2001).

The invention also encompasses kits for using antibodies, such as kitsfor detecting the presence of a variant protein in a test sample. Anexemplary kit can comprise antibodies such as a labeled or labelableantibody and a compound or agent for detecting variant proteins in abiological sample; means for determining the amount, or presence/absenceof variant protein in the sample; means for comparing the amount ofvariant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing theSNP-containing nucleic acid molecules described herein. The term“vector” refers to a vehicle, preferably a nucleic acid molecule, whichcan transport a SNP-containing nucleic acid molecule. When the vector isa nucleic acid molecule, the SNP-containing nucleic acid molecule can becovalently linked to the vector nucleic acid. Such vectors include, butare not limited to, a plasmid, single or double stranded phage, a singleor double stranded RNA or DNA viral vector, or artificial chromosome,such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal elementwhere it replicates and produces additional copies of the SNP-containingnucleic acid molecules. Alternatively, the vector may integrate into thehost cell genome and produce additional copies of the SNP-containingnucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) orvectors for expression (expression vectors) of the SNP-containingnucleic acid molecules. The vectors can function in prokaryotic oreukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions thatare operably linked in the vector to the SNP-containing nucleic acidmolecules such that transcription of the SNP-containing nucleic acidmolecules is allowed in a host cell. The SNP-containing nucleic acidmolecules can also be introduced into the host cell with a separatenucleic acid molecule capable of affecting transcription. Thus, thesecond nucleic acid molecule may provide a trans-acting factorinteracting with the cis-regulatory control region to allowtranscription of the SNP-containing nucleic acid molecules from thevector. Alternatively, a trans-acting factor may be supplied by the hostcell. Finally, a trans-acting factor can be produced from the vectoritself. It is understood, however, that in some embodiments,transcription and/or translation of the nucleic acid molecules can occurin a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acidmolecules described herein can be operably linked include promoters fordirecting mRNA transcription. These include, but are not limited to, theleft promoter from bacteriophage λ, the lac, TRP, and TAC promoters fromE. coli, the early and late promoters from SV40, the CMV immediate earlypromoter, the adenovirus early and late promoters, and retroviruslong-terminal repeats.

In addition to control regions that promote transcription, expressionvectors may also include regions that modulate transcription, such asrepressor binding sites and enhancers. Examples include the SV40enhancer, the cytomegalovirus immediate early enhancer, polyomaenhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation andcontrol, expression vectors can also contain sequences necessary fortranscription termination and, in the transcribed region, aribosome-binding site for translation. Other regulatory control elementsfor expression include initiation and termination codons as well aspolyadenylation signals. A person of ordinary skill in the art would beaware of the numerous regulatory sequences that are useful in expressionvectors (see, e.g., Sambrook and Russell, 2000, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y.).

A variety of expression vectors can be used to express a SNP-containingnucleic acid molecule. Such vectors include chromosomal, episomal, andvirus-derived vectors, for example, vectors derived from bacterialplasmids, from bacteriophage, from yeast episomes, from yeastchromosomal elements, including yeast artificial chromosomes, fromviruses such as baculoviruses, papovaviruses such as SV40, Vacciniaviruses, adenoviruses, poxviruses, pseudorabies viruses, andretroviruses. Vectors can also be derived from combinations of thesesources such as those derived from plasmid and bacteriophage geneticelements, e.g., cosmids and phagemids. Appropriate cloning andexpression vectors for prokaryotic and eukaryotic hosts are described inSambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y.

The regulatory sequence in a vector may provide constitutive expressionin one or more host cells (e.g., tissue specific expression) or mayprovide for inducible expression in one or more cell types such as bytemperature, nutrient additive, or exogenous factor, e.g., a hormone orother ligand. A variety of vectors that provide constitutive orinducible expression of a nucleic acid sequence in prokaryotic andeukaryotic host cells are well known to those of ordinary skill in theart.

A SNP-containing nucleic acid molecule can be inserted into the vectorby methodology well-known in the art. Generally, the SNP-containingnucleic acid molecule that will ultimately be expressed is joined to anexpression vector by cleaving the SNP-containing nucleic acid moleculeand the expression vector with one or more restriction enzymes and thenligating the fragments together. Procedures for restriction enzymedigestion and ligation are well known to those of ordinary skill in theart.

The vector containing the appropriate nucleic acid molecule can beintroduced into an appropriate host cell for propagation or expressionusing well-known techniques. Bacterial host cells include, but are notlimited to, E. coli, Streptomyces, and Salmonella typhimurium.Eukaryotic host cells include, but are not limited to, yeast, insectcells such as Drosophila, animal cells such as COS and CHO cells, andplant cells.

As described herein, it may be desirable to express the variant peptideas a fusion protein. Accordingly, the invention provides fusion vectorsthat allow for the production of the variant peptides. Fusion vectorscan, for example, increase the expression of a recombinant protein,increase the solubility of the recombinant protein, and aid in thepurification of the protein by acting, for example, as a ligand foraffinity purification. A proteolytic cleavage site may be introduced atthe junction of the fusion moiety so that the desired variant peptidecan ultimately be separated from the fusion moiety. Proteolytic enzymessuitable for such use include, but are not limited to, factor Xa,thrombin, and enterokinase. Typical fusion expression vectors includepGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amann etal., Gene 69:301-315 (1988)) and pET 11d (Studier et al., GeneExpression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host byproviding a genetic background wherein the host cell has an impairedcapacity to proteolytically cleave the recombinant protein (Gottesman,S., Gene Expression Technology: Methods in Enzymology 185, AcademicPress, San Diego, Calif. (1990) 119-128). Alternatively, the sequence ofthe SNP-containing nucleic acid molecule of interest can be altered toprovide preferential codon usage for a specific host cell, for example,E. coli (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

The SNP-containing nucleic acid molecules can also be expressed byexpression vectors that are operative in yeast. Examples of vectors forexpression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari, etal., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2(Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed ininsect cells using, for example, baculovirus expression vectors.Baculovirus vectors available for expression of proteins in culturedinsect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,Mol. Cell Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al.,Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acidmolecules described herein are expressed in mammalian cells usingmammalian expression vectors. Examples of mammalian expression vectorsinclude pCDM8 (Seed, B. Nature 329:840 (1987)) and pMT2PC (Kaufman etal., EMBO J. 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containingnucleic acid molecules described herein are cloned into the vector inreverse orientation, but operably linked to a regulatory sequence thatpermits transcription of antisense RNA. Thus, an antisense transcriptcan be produced to the SNP-containing nucleic acid sequences describedherein, including both coding and non-coding regions. Expression of thisantisense RNA is subject to each of the parameters described above inrelation to expression of the sense RNA (regulatory sequences,constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing thevectors described herein. Host cells therefore include, for example,prokaryotic cells, lower eukaryotic cells such as yeast, othereukaryotic cells such as insect cells, and higher eukaryotic cells suchas mammalian cells.

The recombinant host cells can be prepared by introducing the vectorconstructs described herein into the cells by techniques readilyavailable to persons of ordinary skill in the art. These include, butare not limited to, calcium phosphate transfection,DEAE-dextran-mediated transfection, cationic lipid-mediatedtransfection, electroporation, transduction, infection, lipofection, andother techniques such as those described in Sambrook and Russell, 2000,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

Host cells can contain more than one vector. Thus, differentSNP-containing nucleotide sequences can be introduced in differentvectors into the same cell. Similarly, the SNP-containing nucleic acidmolecules can be introduced either alone or with other nucleic acidmolecules that are not related to the SNP-containing nucleic acidmolecules, such as those providing trans-acting factors for expressionvectors. When more than one vector is introduced into a cell, thevectors can be introduced independently, co-introduced, or joined to thenucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introducedinto cells as packaged or encapsulated virus by standard procedures forinfection and transduction. Viral vectors can be replication-competentor replication-defective. In the case in which viral replication isdefective, replication can occur in host cells that provide functionsthat complement the defects.

Vectors generally include selectable markers that enable the selectionof the subpopulation of cells that contain the recombinant vectorconstructs. The marker can be inserted in the same vector that containsthe SNP-containing nucleic acid molecules described herein or may be ina separate vector. Markers include, for example, tetracycline orampicillin-resistance genes for prokaryotic host cells, anddihydrofolate reductase or neomycin resistance genes for eukaryotic hostcells. However, any marker that provides selection for a phenotypictrait can be effective.

While the mature variant proteins can be produced in bacteria, yeast,mammalian cells, and other cells under the control of the appropriateregulatory sequences, cell-free transcription and translation systemscan also be used to produce these variant proteins using RNA derivedfrom the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult toachieve with multi-transmembrane domain containing proteins such asG-protein-coupled receptors (GPCRs), appropriate secretion signals canbe incorporated into the vector. The signal sequence can be endogenousto the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the proteincan be isolated from the host cell by standard disruption procedures,including freeze/thaw, sonication, mechanical disruption, use of lysingagents, and the like. The variant protein can then be recovered andpurified by well-known purification methods including, for example,ammonium sulfate precipitation, acid extraction, anion or cationicexchange chromatography, phosphocellulose chromatography,hydrophobic-interaction chromatography, affinity chromatography,hydroxylapatite chromatography, lectin chromatography, or highperformance liquid chromatography.

It is also understood that, depending upon the host cell in whichrecombinant production of the variant proteins described herein occurs,they can have various glycosylation patterns, or may benon-glycosylated, as when produced in bacteria. In addition, the variantproteins may include an initial modified methionine in some cases as aresult of a host-mediated process.

For further information regarding vectors and host cells, see CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins describedherein have a variety of uses. For example, the cells are useful forproducing a variant protein that can be further purified into apreparation of desired amounts of the variant protein or fragmentsthereof. Thus, host cells containing expression vectors are useful forvariant protein production.

Host cells are also useful for conducting cell-based assays involvingthe variant protein or variant protein fragments, such as thosedescribed above as well as other formats known in the art. Thus, arecombinant host cell expressing a variant protein is useful forassaying compounds that stimulate or inhibit variant protein function.Such an ability of a compound to modulate variant protein function maynot be apparent from assays of the compound on the native/wild-typeprotein, or from cell-free assays of the compound. Recombinant hostcells are also useful for assaying functional alterations in the variantproteins as compared with a known function.

Genetically-engineered host cells can be further used to producenon-human transgenic animals. A transgenic animal is preferably anon-human mammal, for example, a rodent, such as a rat or mouse, inwhich one or more of the cells of the animal include a transgene. Atransgene is exogenous DNA containing a SNP of the present inventionwhich is integrated into the genome of a cell from which a transgenicanimal develops and which remains in the genome of the mature animal inone or more of its cell types or tissues. Such animals are useful forstudying the function of a variant protein in vivo, and identifying andevaluating modulators of variant protein activity. Other examples oftransgenic animals include, but are not limited to, non-human primates,sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-humanmammals such as cows and goats can be used to produce variant proteinswhich can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containingnucleic acid molecule into the male pronuclei of a fertilized oocyte,e.g., by microinjection or retroviral infection, and allowing the oocyteto develop in a pseudopregnant female foster animal. Any nucleic acidmolecules that contain one or more SNPs of the present invention canpotentially be introduced as a transgene into the genome of a non-humananimal.

Any of the regulatory or other sequences useful in expression vectorscan form part of the transgenic sequence. This includes intronicsequences and polyadenylation signals, if not already included. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the variant protein in particularcells or tissues.

Methods for generating transgenic animals via embryo manipulation andmicroinjection, particularly animals such as mice, have becomeconventional in the art and are described in, for example, U.S. Pat.Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No.4,873,191 by Wagner et al., and in Hogan, B., Manipulating the MouseEmbryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1986). Similar methods are used for production of other transgenicanimals. A transgenic founder animal can be identified based upon thepresence of the transgene in its genome and/or expression of transgenicmRNA in tissues or cells of the animals. A transgenic founder animal canthen be used to breed additional animals carrying the transgene.Moreover, transgenic animals carrying a transgene can further be bred toother transgenic animals carrying other transgenes. A transgenic animalalso includes a non-human animal in which the entire animal or tissuesin the animal have been produced using the homologously recombinant hostcells described herein.

In another embodiment, transgenic non-human animals can be producedwhich contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinasesystem of bacteriophage P1 (Lakso et al PNAS 89:6232-6236 (1992)).Another example of a recombinase system is the FLP recombinase system ofS. cerevisiae (O'Gorman et al. Science 251:1351-1355 (1991)). If acre/loxP recombinase system is used to regulate expression of thetransgene, animals containing transgenes encoding both the Crerecombinase and a selected protein are generally needed. Such animalscan be provided through the construction of “double” transgenic animals,e.g., by mating two transgenic animals, one containing a transgeneencoding a selected variant protein and the other containing a transgeneencoding a recombinase.

Clones of the non-human transgenic animals described herein can also beproduced according to the methods described in, for example, Wilmut, I.et al. Nature 385:810-813 (1997) and PCT International Publication Nos.WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell)from the transgenic animal can be isolated and induced to exit thegrowth cycle and enter G_(o) phase. The quiescent cell can then befused, e.g., through the use of electrical pulses, to an enucleatedoocyte from an animal of the same species from which the quiescent cellis isolated. The reconstructed oocyte is then cultured such that itdevelops to morula or blastocyst and then transferred to pseudopregnantfemale foster animal. The offspring born of this female foster animalwill be a clone of the animal from which the cell (e.g., a somatic cell)is isolated.

Transgenic animals containing recombinant cells that express the variantproteins described herein are useful for conducting the assays describedherein in an in vivo context. Accordingly, the various physiologicalfactors that are present in vivo and that could influence ligand orsubstrate binding, variant protein activation, signal transduction, orother processes or interactions, may not be evident from in vitrocell-free or cell-based assays. Thus, non-human transgenic animals ofthe present invention may be used to assay in vivo variant proteinfunction as well as the activities of a therapeutic agent or compoundthat modulates variant protein function/activity or expression. Suchanimals are also suitable for assessing the effects of null mutations(i.e., mutations that substantially or completely eliminate one or morevariant protein functions).

For further information regarding transgenic animals, see Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol. 2002 December; 13(6):625-9; Petters etal., “Transgenic animals as models for human disease,” Transgenic Res.2000; 9(4-5):347-51; discussion 345-6; Wolf et al., “Use of transgenicanimals in understanding molecular mechanisms of toxicity,” J PharmPharmacol. 1998 June; 50(6):567-74; Echelard, “Recombinant proteinproduction in transgenic animals,” Curr Opin Biotechnol. 1996 October;7(5):536-40; Houdebine, “Transgenic animal bioreactors,” Transgenic Res.2000; 9(4-5):305-20; Pirity et al., “Embryonic stem cells, creatingtransgenic animals,” Methods Cell Biol. 1998; 57:279-93; and Robl etal., “Artificial chromosome vectors and expression of complex proteinsin transgenic animals,” Theriogenology. 2003 Jan. 1; 59(1):107-13.

EXAMPLES

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Example One SNPs Associated with Deep Vein Thrombosis

Introduction

To identify SNPs associated with DVT, 19,682 SNPs (which were primarilymissense SNPs) were investigated for association with DVT in three largecase-control studies.

Methods

Study Populations and Data Collection

The 3 studies (LETS, MEGA-1 and MEGA-2) in the present analysis arederived from 2 large population-based case-control studies: the LeidenThrombophilia Study (LETS) and the Multiple Environmental and GeneticAssessment of risk factors for venous thrombosis (MEGA study) (Koster etal., Lancet 1993; 342(8886-8887):1503-1506 and Blom et al., JAMA 2005;293(6):715-722). These studies were approved by the Medical EthicsCommittee of the Leiden University Medical Center, Leiden, TheNetherlands. All participants gave informed consent to participate.

LETS Population

Collection and ascertainment of DVT events in LETS has been describedpreviously (Koster et al., Lancet 1993; 342(8886-8887):1503-1506).Briefly, 474 consecutive patients, 70 years or younger, without a knownmalignancy were recruited between Jan. 1, 1988 and Dec. 30, 1992 from 3anticoagulation clinics in The Netherlands. For each patient, an age-and sex-matched control participant without a history of DVT wasenrolled. Participants completed a questionnaire on risk factors for DVTand provided a blood sample. No ethnicity information was collected.After exclusion of 52 participants due to inadequate sample, 443 casesand 453 controls remained in the analyses.

MEGA-1 and MEGA-2 Studies

Collection and ascertainment of DVT events in MEGA has been describedpreviously (Blom et al., JAMA 2005; 293(6):715-722; van Stralen et al.,Arch Intern Med 2008; 168(1):21-26). MEGA enrolled consecutive patientsaged 18 to 70 years who presented with their first diagnosis of DVT orpulmonary embolism (PE) at any of 6 anticoagulation clinics in TheNetherlands between Mar. 1, 1999 and May 31, 2004. Control subjectsincluded partners of patients and random population control subjectsfrequency-matched on age and sex to the patient group. Participantscompleted a questionnaire on risk factors for DVT and provided a bloodor buccal swab sample. The questionnaire included an item on parentbirth country as a proxy for ethnicity.

For the present analyses, the MEGA study was split to form 2case-control studies, based on recruitment date and sample availability(blood or buccal swab). Individuals with isolated pulmonary embolism ora history of malignant disorders were excluded in order to obtain astudy population similar to the LETS population. The first subset ofMEGA, “MEGA-1”, included 1398 cases and 1757 controls who had alldonated blood samples. The remaining 1314 cases and 2877 controls, whodonated either a blood sample or a buccal swab sample, were included in“MEGA-2”.

Baseline characteristics of the participants in the studies describedabove are presented in Table 5.

SNP Association Study

The 19,682 SNPs tested in this study are located in 10,887 genes andwere selected because of their potential to affect gene function orexpression (Shiffman et al., Am J Hum Genet 2005; 77(4):596-605). MostSNPs (69%) are missense. Another 24% of the SNPs are located intranscription factor binding sites or in untranslated regions of mRNA,which could affect mRNA expression or stability. 91% of the SNPs studiedhave minor allele frequencies≧5% in whites.

The design of the SNP association study is presented in FIG. 1. First,all 19,682 SNPs were tested in pooled DNA samples of LETS. SNPs thatwere associated with DVT (P≦0.05) were tested in pooled DNA samples ofMEGA-1. SNPs that were associated in both LETS and MEGA-1 pools (P≦0.05)were confirmed by genotyping individual samples of LETS and MEGA-1. SNPgenotypes consistently associated with DVT in LETS and MEGA-1 (P≦0.05)were genotyped in MEGA-2.

Allele Frequency and Genotype Determination

DNA concentrations were standardized to 10 ng/μL using PicoGreen(Molecular Probes, Invitrogen Corp, Carlsbad, Calif.) fluorescent dye.DNA pools, typically of 30-100 samples, were assembled based oncase-control status, sex, age and factor V Leiden status. DNA pools weremade by mixing equal volumes of standardized DNA solution from eachindividual sample. Each allele was amplified separately by PCR using 3ng of pooled DNA. In the pooled stage, 6 case pools and 4 control poolswere used for LETS, and 13 case pools and 18 control pools were used forMEGA-1. Allele frequencies in pooled DNA were determined by kineticpolymerase chain reaction (kPCR) (Germer et al., Genome Res 2000;10(2):258-266). Duplicate kPCR assays were run for each allele and theamplification curves from these assays were used to calculate the allelefrequencies of the SNP (Germer et al., Genome Res 2000; 10(2):258-266).Genotyping of individual DNA samples was similarly performed using 0.3ng of DNA in kPCR assays or using multiplexed oligo ligation assays(OLA) (Shiffman et al., Arterioscler Thromb Vasc Biol 2008;28(1):173-179). Genotyping accuracy of the multiplex methodology andkPCR has been assessed in 3 previous studies and the overall concordanceof the genotype calls from these two methods was >99% (Shiffman et al.,Am J Hum Genet 2005; 77(4):596-605; Iakoubova et al., ArteriosclerThromb Vasc Biol 2006; 26(12):2763-2768; and Shiffman et al.,Arterioscler Thromb Vasc Biol 2006; 26(7):1613-1618). The SNPsassociated with DVT in MEGA-2 were successfully genotyped in >95% of thesubjects in LETS, MEGA-1 and MEGA-2.

Gene Variants and DVT Risk in the CYP4V2 Region

The rs13146272 SNP in the gene CYP4V2 was most strongly associated withDVT in the SNP association study. To investigate whether other SNPs inthis region are associated with DVT, results from the HapMap Projectwere used to identify a region surrounding rs13146272 (chr4:187,297,249-187,467,731) (Nature 2005; 437(7063):1299-1320). Thisregion contained 149 SNPs with allele frequencies>2% (HapMap NCBI build36). Allele frequencies and linkage disequilibrium were calculated fromthe SNP genotypes in the HapMap CEPH population, which includes Utahresidents with ancestry from northern and western Europe. 48 of these149 SNPs were selected for genotyping, as surrogates for 142 of the 149SNPs in this region that were either directly genotyped or in stronglinkage disequilibrium (r²>0.8) with at least one of the 48 genotypedSNPs (the remaining 7 of the 149 SNPs were in low linkage disequilibriumwith rs13146272 (r²<0.2) and therefore not likely to be the cause of theobserved association). The 48 SNPs were chosen using pairwise tagging inTagger (implemented in Haploview) (Barrett et al., Bioinformatics 2005;21(2):263-265).

The 48 SNPs were initially investigated in LETS, and SNPs that wereequally or more strongly associated with DVT than rs13146272 wereinvestigated in MEGA-1.

Factor XI Assays

Factor XI antigen measurements in LETS were described previously(Meijers et al., N Engl J Med 2000; 342(10):696-701). In MEGA, factor XIlevels were measured on a STA-R coagulation analyzer (Diagnostica Stago,Asnières, France). STA CaCl₂ solution was used as an activator, STAUnicalibrator was used as a reference standard and Preciclot plus I(normal factor XI range) was used as control plasma. The intra-assaycoefficient of variation (CV) was 5.8% (10 assays). The inter-assay CVwas 8.7% (48 assays).

Statistical Analysis

Deviations from Hardy-Weinberg expectations were assessed using an exacttest in controls (Weir, Genetic Data Analysis II Sunderland: SinauerAssociates Inc 1996). For pooled DNA analysis, a Fisher's exact test wasused to evaluate allele frequency differences between cases andcontrols. For the final set of SNPs presented in Table 6, logisticregression models were used to calculate the odds ratio (OR), 95%confidence interval (95% CI) and 2-sided P-value for the association ofeach SNP with DVT and to adjust for age and sex. For each SNP, the ORper genotype relative to non-carriers of the risk allele, and the riskallele OR from an additive model, were calculated. This risk allele ORcan be interpreted as the risk increase per copy of the risk allele, andthe corresponding P-value was used to decide whether the SNP wasassociated with DVT (P≦0.05). For SNPs on the X chromosome the analysiswas conducted separately in men and women.

The OR (95% CI) for SNPs in the CYP4V2 region was estimated by logisticregression with adjustment for factor XI levels and other SNPs in theregion. Differences in factor XI level between groups were tested witht-tests, and changes in factor XI level per allele were estimated bylinear regression. Analyses were done with SAS version 9 and SPSS forWindows, 14.0.2 (SPSS Inc, Chicago, Ill.).

False Discovery Rate

Studies of thousands of SNPs can lead to false-positive associations.Therefore, 2 replications were performed after the initial discoverystage in LETS and the false discovery rate was calculated for the SNPsgenotyped in MEGA-2. The false discovery rate estimates the expectedfraction of false positives among a group of SNPs; and is a function ofthe P-values and the number of tests (Benjamini et al., Journal of theRoyal Statistical Society 1995; (Serials B(57)):1289-1300). Falsediscovery rates were estimated using the 2-sided, unadjusted P-valuefrom the additive model. A false discovery rate of 0.10 was used as acriterion for further analysis (for a false discovery rate of 0.10, onewould expect 10% of the SNPs in the group considered associated to befalse positives).

Results

SNPs Associated with DVT in LETS and MEGA-1

In LETS 19,682 SNPs were investigated by comparing the allelefrequencies of patients and controls using pooled DNA samples (Germer etal., Genome Res 2000; 10(2):258-266). It was found that 1206 of these19,682 SNPs were associated (P≦0.05) with DVT. These 1206 SNPs were theninvestigated in patients and controls from MEGA-1 using pooled DNAsamples. SNPs that were associated with DVT in both LETS and MEGA-1 wereconfirmed by genotyping in both studies, and it was found that 18 SNPswere consistently (with the same risk allele) associated with DVT(P≦0.05) in both LETS and MEGA-1 (Table 6).

SNPs Associated with DVT in MEGA-2

Nine of these 18 SNPs were subsequently tested in MEGA-2 for associationwith DVT (Table 7); assays for the other 9 SNPs were not available atthe time. The genotypes of these 9 SNPs did not deviate fromHardy-Weinberg equilibrium (P≦0.01) in the LETS and MEGA controls.

To account for the many tests, the false discovery rate was estimatedfor the SNPs tested in MEGA-2. In Table 6, factor V Leiden and theprothrombin G20210A mutation are presented for reference, but sincethese variants were not included in the SNP association study, theirfalse discovery rate was not calculated. For the SNP in F9 (rs6048),only men were included because no association with DVT was observed inwomen in LETS and MEGA-1. It was found that 3 SNPs were again associatedwith DVT in MEGA-2 (P<0.05), with false discovery rates≦0.10. These 3SNPs were in the genes CYP4V2, SERPINC1 and GP6. The 4 SNPs with thenext lowest P-values (ranging from 0.06 to 0.15) also had low falsediscovery rates (≦0.20). These SNPs were in the genes RGS7, NR1I2, NAT8Band F9. The risk allele frequencies for these 7 SNPs ranged from 10% to82% among the controls. The OR for homozygous carriers, compared withhomozygotes of the other allele, ranged from 1.19 to 1.49. The 2 SNPsmost strongly associated with DVT were in CYP4V2 (rs13146272, P<0.001,false discovery rate 0.0006) and SERPINC1 (rs2227589, P<0.001, falsediscovery rate 0.004).

For the two SNPs on chromosome 1 (rs2227589 and rs670659), linkagedisequilibrium with the factor V Leiden (FVL) variant was investigated.The SNP (rs2227589) in SERPINC1, which encodes antithrombin, is 4.37megabases away from the FVL variant. The SNP in RGS7 (rs670659) is 71.48megabases from FVL. Each was in weak linkage-disequilibrium with FVL(r²<0.01). Restricting analyses to non-carriers of FVL did notappreciably change the risk estimate of either SNP.

SNPs in CYP4V2 Region and DVT Risk

The SNP with the strongest association with DVT was rs13146272, locatedin the gene encoding a member of the cytochrome P450 family 4 (CYP4V2).48 SNPs in this region were genotyped in the LETS population and the ORfor DVT per copy of the risk-increasing allele was estimated. For manyof the 48 SNPs, including rs13146272, the common allele was the riskallele. In LETS, rs13146272 had an OR for DVT of 1.22 (95% CI,1.00-1.49). Higher ORs were observed for 9 of the other SNPs tested inthis region. These SNPs were located in the CYP4V2, KLKB1 (coding forprekallikrein) and F11 (coding for coagulation factor XI) genes.

9 of the 48 SNPs that had an OR>1.22 (the OR of rs13146272) were thenselected and investigated in MEGA-1. It was found that 5 of these SNPswere associated with DVT in both LETS and MEGA-1: rs13146272, rs3087505,rs3756008, rs2036914 and rs4253418 (Table 8). The rs3087505 SNP in KLKB1had the highest risk estimate: OR 3.61 (95% CI, 1.48-8.82) for the majorallele homozygotes versus minor allele homozygotes. Mutual adjustmentamong these 5 SNPs did not indicate that any of these 5 associationswere explained by the other 4 SNPs.

SNPs in CYP4V2 Region and Factor XI Levels

Because the F11 gene is located close to rs13146272 and because factorXI levels have been previously reported to be associated with DVT in theLETS population, it was investigated whether an association between SNPsand factor XI levels explained the association between the SNPs and DVT(Meijers et al., N Engl J Med 2000; 342(10):696-701). In LETS, factor XIlevels above the 90^(th) percentile had been shown to be associated witha 2-fold increased risk of DVT (Meijers et al., N Engl J Med 2000;342(10):696-701). It was found that high factor XI levels (>90^(th)percentile) were also associated with DVT in MEGA (OR 1.9, 95% CI,1.6-2.3).

Only 9 of the 18 stage 3 SNPs were indeed tested in MEGA-2 DNA in stage4. The reason for this was that in order to save MEGA-2 DNA, stage 4SNPs were genotyped using multiplexed oligo ligation assays, and assaysfor only 9 stage 3 SNPs were available at the time of this study.

The 7 SNPs from the CYP4V2 region that were associated with DVT were allassociated with factor XI levels in LETS and MEGA-1, with higher factorXI levels for those who carried the risk-increasing alleles (Table 8).It was investigated whether factor XI levels mediate the associationbetween these 5 SNPs and DVT by adjusting for factor XI levels in thecombined LETS and MEGA-1 studies. For all 5 SNPs, adjustment for factorXI levels weakened the association with DVT but none of the associationsdisappeared. Interestingly, the 5 SNPs that were not associated with DVTin the combined analysis of LETS and MEGA-1 (rs3736456, rs4253259,rs4253408, rs4253325 and rs3775302) were also not associated with factorXI levels in LETS.

All analyses were performed with and without adjustment for age and sex,and analyses in MEGA-1 and MEGA-2 were performed with and withoutrestriction to the group with both parents born in North-West Europe. Asneither influenced the results, the unadjusted OR is presented.

Discussion

7 SNPs were identified that were associated with DVT in 3 large, wellcharacterized populations including 3155 cases and 5087 controls. Theevidence was strongest for the 3 SNPs in CYP4V2, SERPINC1 and GP6. It isinteresting to note that these SNPs are in or near genes that have aclear role in blood coagulation.

Testing 19,682 SNPs will result in false positive associations.Therefore, the SNPs were investigated in 3 large studies and the falsediscovery rate for the SNPs tested was estimated in the third study. Thethree SNPs in CYP4V2, SERPINC1 and GP6, were associated with DVT with afalse discovery rate<10%, which means that <10% of these 3 SNPs would beexpected to be false positive. Relaxing the false discovery rate to <20%would add 4 SNPs, in RGS7, NR1I2, NAT8B, and F9 as associated with DVT.

The 3 SNPs with the strongest evidence for association with DVT were inCYP4V2, SERPINC1, and GP6. CYP4V2 encodes a member of the CYP450 family4 that is not known to be related to thrombosis (Lee et al., InvestOpthalmol Vis Sci 2001; 42(8):1707-1714 and Li et al., Am J Hum Genet2004; 74(5):817-826). CYP4V2 is located on chromosome 4 in a regioncontaining genes encoding coagulation proteins prekallikrein (KLKB1) andfactor XI (F11). 4 other SNPs in the CYPV42/KLKB1/F11 locus were alsoidentified as being associated with DVT. No previous reports exist foran association of genetic variants in CYP4V2 and KLKB1 with DVT. Thereexists no evidence for an association between prekallikrein levels andDVT, while there is for elevated factor XI levels (Souto et al., Am JHum Genet 2000; 67(6):1452-1459; Meijers et al., N Engl J Med 2000;342(10):696-701; and Gallimore et al., Thromb Res 2004; 114(2):91-96).

SERPINC1 encodes antithrombin, a serine protease inhibitor located onchromosome 1 that plays a central role in natural anticoagulation.Deficiencies of antithrombin are rare but result in a strong thrombotictendency (Gallimore et al., Thromb Res 2004; 114(2):91-96). The SNP inSERPINC1 (rs2227589) had a minor allele frequency of 10% in the controlsand was associated with a modest thrombotic tendency. GP6 encodesglycoprotein VI, a 58-kD platelet membrane glycoprotein that plays acrucial role in the collagen-induced activation and aggregation ofplatelets and may play a role in DVT (Massberg et al., J Exp Med 2003;197(1):41-49 and Chung et al., J Thromb Haemost 2007; 5(5):918-924).

The SNPs in the genes F9, NR1I2, RGS7 and NA T8B are of interest. F9encodes factor IX, a vitamin K-dependent clotting factor, of which highlevels have been shown to increase the risk of DVT (van Hylckama Vlieget al., Blood 2000; 95(12):3678-3682). The SNP rs6048, also known as F9Malmö, is a common polymorphism at the third amino acid residue of theactivation peptide of factor IX (McGraw et al., Proc Natl Acad Sci US A1985; 82(9):2847-2851).

The SNP in CYP4V2 (rs13146272) is located close to the gene encodingcoagulation factor XI. Factor XI levels have been reported to beassociated with DVT in LETS and in a large analysis of pedigrees (Soutoet al., Am J Hum Genet 2000; 67(6):1452-1459 and Meijers et al., N EnglJ Med 2000; 342(10):696-701). The association between DVT and factor XIlevels was confirmed in MEGA. Interestingly, the 5 SNPs in the CYP4V2region that were associated with DVT in both LETS and MEGA-1 were alsoassociated with factor XI levels. However, the association between these5 SNPs and DVT does not seem to be completely explained by variation infactor XI levels because adjusting for factor XI level did not removethe excess DVT risk of these 5 SNPs. Thus, if only part of the riskassociated with these genetic variants is mediated through levels offactor XI, some of the risk might also be due to effects on proteinfunction.

Several variants in the F11 gene (rs5974, rs5970, rs5971, rs5966,rs5976, and rs5973) were previously tested for association with factorXI levels in patients with DVT and atherosclerosis, but no relationshipwas observed (Gerdes et al., J Thromb Haemost 2004; 2(6): 1015-1017). Inthe present study, rs5974 (r²=1.0 with 5970) and rs5971 (r²=1.0 with5966 and rs5976) were not associated with DVT in LETS. rs5973 was notgenotyped because its minor allele frequency was lower than 2% (HapMapCEPH population). In a study of West African volunteers, rs3822056 andrs3733403 were associated with transcription factor binding affinity andslightly increased factor XI levels, but neither SNP was associated withDVT in LETS. In a study among white postmenopausal women, rs3822057 andrs2289252 were associated with DVT (Tarumi et al., J Thromb Haemost2003; 1(8):1854-1856 and Smith et al., JAMA 2007; 297(5):489-498). Bothof these associations were indirectly confirmed in the present studybecause 2 of the 5 SNPs in the CYPV42 region that were consistentlyassociated with DVT and factor XI levels are in linkage disequilibriumwith rs3822057 (r²=0.9 with rs2036914) and rs2289252 (r²=0.8 withrs3756008).

Since the variants described herein are common, they may be particularlyuseful markers for determining DVT risk, especially when combined withother risk factors.

This analysis was limited to a North-West European population. In LETS,no information on ethnicity was collected. However, it is thought thatpopulation stratification did not bias the results because MEGAparticipants were recruited from the same population as LETS but 10years later and 90% of MEGA had both parents born in North-West Europe.Furthermore, restricting the analyses to this 90% of MEGA did not modifythe results.

Conclusions

Thousands of SNPs were tested for association with DVT in unrelatedindividuals, and 7 of these SNPs were found to be consistentlyassociated with DVT risk. In the CYP4V2 region, several SNPs wereidentified that were associated with both DVT and factor XI levels.

TABLE 5 Characteristics of Cases and Controls in LETS, MEGA-1, andMEGA-2 LETS MEGA-1 MEGA-2 Cases Controls Cases Controls Cases Controls(n = 443) (n = 453) (n = 1398) (n = 1757) (n = 1314) (n = 2877) Men, No.(%) 190 (43) 192 (42) 652 (47) 843 (48) 633 (48) 1348 (47) Age, Mean(SD)  45 (14)  45 (14)  47 (13)  48 (12)  48 (13)  47 (12) Both parentsborn — — 1247 (91)  1609 (92)  1149 (90)  2527 (89) in North-WestEurope, N (%)^(a) ^(a)No information on birth country was collected inLETS.

TABLE 6 Association of 18 SNPs from the SNP association study and factorV Leiden and prothrombin G20210A with DVT in LETS and MEGA-1. Riskallele Chr Gene SNP ID SNP Type^(a) Study Case (%) Control (%) OR^(b)(95% CI) P-Value 3 NR1I2 rs1523127 5′UTR LETS C 373 (42) 300 (33) 1.44(1.19-1.73) <.001 MEGA-1 1185 (42) 1373 (39) 1.15 (1.04-1.27) .008 19GP6 rs1613662 Ser219Pro LETS A 749 (85) 725 (80) 1.36 (1.07-1.74) .01MEGA-1 2318 (84) 2823 (81) 1.21 (1.06-1.38) .004 17 APOH rs1801690Ser335Trp LETS C 850 (97) 852 (95) 1.65 (1.02-2.68) .04 MEGA-1 2676 (96)3312 (94) 1.42 (1.12-1.79) .004 2 NAT8B rs2001490 Ala112Gly LETS C 382(43) 348 (38) 1.23 (1.01-1.49) .04 MEGA-1 1118 (40) 1301 (37) 1.14(1.03-1.26) .01 1 SERPINC1 rs2227589 Intronic LETS T 105 (12) 78 (9)1.42 (1.04-1.94) .03 MEGA-1 303 (11) 313 (9) 1.24 (1.05-1.47) .01 7 METrs2237712 Intronic LETS G 45 (5) 27 (3) 1.68 (1.05-2.70) .03 MEGA-1 119(4) 110 (3) 1.38 (1.06-1.80) .02 11 EPS8L2 rs3087546 Leu101Leu LETS T522 (60) 487 (54) 1.26 (1.04-1.52) .02 MEGA-1 1637 (59) 1964 (56) 1.12(1.01-1.24) .03 6 CASP8AP2 rs369328 Lys93Lys LETS A 461 (52) 406 (45)1.35 (1.11-1.63) .002 MEGA-1 1420 (51) 1680 (48) 1.13 (1.02-1.24) .02 1SELP rs6131 Asn331Ser LETS T 196 (22) 161 (18) 1.29 (1.03-1.62) .03MEGA-1 589 (21) 636 (18) 1.21 (1.06-1.36) .003 19 ZNF544 rs6510130Asp203His LETS G 33 (4) 13 (1) 2.54 (1.34-4.83) .004 MEGA-1 78 (3) 64(2) 1.56 (1.11-2.18) .01 1 RGS7 rs670659 Intronic LETS C 617 (70) 584(64) 1.27 (1.04-1.54) .02 MEGA-1 1864 (67) 2249 (64) 1.13 (1.01-1.25).03 2 TACR1 rs881 3′UTR LETS C 745 (85) 713 (80) 1.38 (1.07-1.77) .01MEGA-1 2356 (85) 2894 (83) 1.15 (1.01-1.32) .04 4 CYP4V2 rs13146272Lys259Gln LETS A 611 (69) 588 (65) 1.22 (1.00-1.49) .05 MEGA-1 1896 (68)2245 (64) 1.19 (1.07-1.32) .001 1 F5 rs4524 Arg858Lys LETS T 708 (80)671 (74) 1.36 (1.09-1.69) .006 MEGA-1 2184 (79) 2608 (74) 1.26(1.12-1.42) <.001 1 SMOYKEEBO/F5 rs6016 Ile736Ile LETS G 704 (80) 668(74) 1.35 (1.09-1.69) .006 MEGA-1 2188 (79) 2615 (75) 1.27 (1.13-1.43)<.001 1 C1orf114 rs3820059 Ser172Phe LETS A 320 (36) 269 (30) 1.34(1.10-1.64) .004 MEGA-1 1065 (38) 1169 (33) 1.22 (1.10-1.35) <.001 X F9rs6048 Ala194Thr LETS Men A 146 (77) 128 (67) 1.74 (1.10-2.74) .02 LETSWomen 225 (70) 238 (68) 1.09 (0.84-1.42) .50 MEGA-1 464 (73) 566 (68)1.26 (1.00-1.58) .05 Men MEGA-1 674 (72) 818 (71) 1.04 (0.90-1.21) .61Women X ODZ1 rs2266911 Intronic LETS Men C 161 (85) 147 (77) 1.66(0.99-2.79) .06 LETS Women 422 (83) 418 (80) 1.26 (0.91-1.73) .17 MEGA-1556 (85) 671 (80) 1.47 (1.12-1.94) .006 Men MEGA-1 1234 (82) 1430 (78)1.25 (1.05-1.48) .01 Women 1 F5 (Leiden) rs6025 Arg534Gln LETS A 95 (11)14 (2) 7.19   (4.05-(12.77) <.001 MEGA-1 291 (10) 96 (3) 4.10(3.23-5.21) <.001 11 F2 (G20210A) rs1799963 3′UTR LETS A 28 (3) 10 (1)2.98 (1.43-6.20) <.001 MEGA-1 81 (3) 37 (1) 2.89 (1.94-4.29) <.001 Chrdenotes chromosome number. All gene symbols, rs numbers, SNP types andchromosome numbers are from NCBI build 36. ^(a)The first amino acidcorresponds to the non risk allele. ^(b)OR were estimated by logisticregression using an additive model. Sex was included as a covariate inlogistic regression models containing markers residing on the Xchromosome and the number of risk alleles for these SNPs were coded as 0or 1 for males and 0, 1 or 2 for females.

TABLE 7 Associations of SNPs from the SNP Association Study With DeepVein Thrombosis in MEGA-2 Chr Gene SNP Risk allele^(a) Genotype^(b)Case, N (%)^(c) Control, N (%)^(c) OR (95% CI) P value FDR^(d)  4 CYP4V2rs13146272 A CC 121 (10) 352 (13)    1 (ref) CA 478 (41) 1178 (45)  1.18 (0.94-1.49) AA 561 (48) 1094 (42)   1.49 (1.19-1.88) Additive (69)(64)  1.24 (1.11-1.37) <.001 <.001  1 SERPINC1 rs2227589 T CC 1001 (77) 2325 (82)     1 (ref) CT 278 (21) 483 (17)  1.34 (1.13-1.58) TT 15 (1)28 (1)  1.24 (0.66-2.34) Additive (12) (11)  1.29 (1.10-1.49) <.0010.004 19 GP6 rs1613662 A GG 29 (2) 89 (3)    1 (ref) GA 355 (27) 835(29)  1.31 (0.84-2.02) AA 915 (70) 1924 (68)   1.46 (0.95-2.24) Additive(84) (82)  1.15 (1.01-1.30) 0.03 0.10  1 RGS7 rs670659 C TT 129 (10) 355(13)    1 (ref) TC 615 (48) 1326 (47)   1.28 (1.02-1.60) CC 548 (42)1153 (41)   1.31 (1.04-1.64) Additive (66) (64)  1.10 (1.00-1.22) 0.060.13  3 NR1I2 rs1523127 C AA 480 (37) 1097 (39)     1 (ref) AC 598 (46)1340 (47)   1.02(0.88-1.18) CC 220 (17) 409 (14)  1.23 (1.01-1.50)Additive (40) (38)  1.09 (0.99-1.20) 0.07 0.13  2 NAT8B rs2001490 C GG490 (38) 1122 (39)     1 (ref) GC 603 (46) 1334 (47)  1.04 (0.90-1.19)CC 205 (16) 394 (14)  1.19 (0.98-1.45) Additive (39) (37)  1.08(0.98-1.19) 0.12 0.18 X F9 (men) rs6048 A Additive (73) (70)  1.17(0.94-1.445) 0.15 0.20 X F9 (women) rs6048 A GG 56 (8) 148 (10)    1(ref) GA 275 (41) 615 (41)  1.18 (0.84-1.66) AA 343 (51) 752 (50)  1.21(0.86-1.68) Additive (71) (70)  1.07 (0.93-1.23) 0.37 NA 19 ZNF544rs6510130 G CC 1192 (95)  2626 (95)     1 (ref) CG 60 (5) 137 (5)   0.97(0.71-1.32) GG  0 (0)  4 (0) — Additive  (2)  (3)  0.91 (0.67-1.24) 0.560.63  7 MET rs2237712 G AA 1183 (93)  2528 (93)     1 (ref) AG 86 (7)184 (7)   1.00 (0.77-1.30) GG  3 (0)  3 (0)  2.14 (0.43-10.6) Additive (4)  (4)  1.03 (0.80-1.33) 0.79 0.79 11 F2 rs1799963 A GG 1219 (94) 2794 (98)     1 (ref) GA 76 (6) 55 (2)  3.17 (2.22-4.51) AA  0 (0)  0(0) — Additive  (3)  (1)  3.17 (2.22-4.51) <.001 NA^(f)  1 F5 rs6025 AGG 1029 (81)  2646 (95)     1 (ref) GA 235 (18) 140 (5)   4.32(3.46-5.39) AA  8 (0)  2 (0) 10.30 (2.18-48.52) Additive (10)  (3)  4.24(3.42-5.26) <.001 NA^(f) Abbreviations: OR, odds ratio; CI, confidenceinterval; FDR, false discovery rate; NA, not applicable, not in FDRanalysis. ^(a)Risk increasing allele identified in LETS and MEGA-1.^(b)In the additive model, the increase in risk per copy of the riskallele is calculated ^(c)For the additive model, only the allelefrequency is presented, not the count. ^(d)P value from the additivemodel was used for FDR estimation. ^(e)All gene symbols and rs numbersare from NCBI build 36. ^(f)Factor V Leiden and the prothrombin G20210Amutation are presented for reference. Since these variants were notincluded in the SNP association study, their false discovery rate wasnot calculated.

TABLE 8 Association of SNPs in CYP4V2 region with DVT and Factor XIlevels in the combined LETS and MEGA-1 studies. FXI^(a) Risk Control, %difference Deep Vein Thrombosis SNP Gene allele Genotype Case, N (%) N(%) (95% CI) OR (95% CI) OR^(b) (95% CI) rs13146272 CYP4V2 A CC 181 (10)293 (13) reference   1 (reference)   1 (reference) CA 808 (44) 995 (45) 3 (1-6) 1.32 (1.07-1.62) 1.26 (1.03-1.56) AA 850 (46) 919 (42)  7 (4-9)1.50 (1.22-1.84) 1.36 (1.10-1.68) Additive (68) (64)  3 (2-4) 1.20(1.09-1.31) 1.14 (1.04-1.25) rs3736456^(c) CYP4V2 T CC  7 (0)  0 (0) CT162 (9) 222 (10) reference   1 (reference)   1 (reference) TT 1663 (91) 1973 (90)   1 (−1-4) 1.16 (0.93-1.43) 1.15 (0.93-1.42) Additive (95)(95)  1 (−2-4) 1.06 (0.86-1.30) 1.05 (0.85-1.28) rs3087505 KLKB1 C TT  6(0)  25 (1) reference   1 (reference)   1 (reference) TC 317 (17) 438(20)  11 (6-16) 3.02 (1.22-7.44) 2.59 (1.05-6.40) CC 1509 (82)  1743(79)   19 (14-24) 3.61 (1.48-8.82) 2.81 (1.15-6.89) Additive (91) (89) 8 (6-10) 1.27 (1.09-1.47) 1.15 (0.99-1.34) rs4253259 KLKB1 C AA  5 (0) 6 (0) reference   1 (reference)   1 (reference) AC 168 (9)  219 (10)  0(−18-18) 0.92 (0.28-3.07) 0.95 (0.28-3.20) CC 1652 (91)  1978 (90)   0(−19-18) 1.00 (0.31-3.29) 1.03 (0.31-3.43) Additive (95) (95)  0 (−3-2)1.08 (0.88-1.32) 1.08 (0.88-1.32) rs4253408 F11 A GG 1526 (83)  1869(85)  reference   1 (reference)   1 (reference) GA 293 (16) 317 (14)  4(2-6) 1.13 (0.95-1.35) 1.06 (0.89-1.27) AA 15 (1) 17 (1)  13 (−1-27)1.08 (0.54-2.17) 0.97 (0.48-1.98) Additive  (9)  (8)  5 (3-7) 1.11(0.95-1.30) 1.05 (0.89-1.23) rs4253325 F11 G AA 21 (1) 23 (1) reference  1 (reference)   1 (reference) AG 308 (17) 392 (18)  5 (0-16) 0.86(0.47-1.58) 0.86 (0.46-1.59) GG 1507 (82)  1785 (81)   8 (−3-13) 0.93(0.51-1.68) 0.88 (0.48-1.62) Additive (90) (90)  3 (1-5) 1.05(0.91-1.21) 1.01 (0.87-1.17) rs3775302 KLKB1 A GG 1418 (77)  1686 (77) reference   1 (reference)   1 (reference) GA 380 (21) 481 (22)  −1(−3-1) 0.94 (0.81-1.09) 0.97 (0.83-1.13) AA 38 (2) 34 (2)  −4 (−11-3)1.33 (0.83-2.12) 1.34 (0.83-2.14) Additive (12) (12)  −1(−3-0) 1.00(0.87-1.14) 1.02 (0.89-1.16) rs3756008 F11 T AA 526 (29) 788 (36)reference   1 (reference)   1 (reference) AT 903 (49) 1032 (47)   7(6-9) 1.31 (1.14-1.51) 1.21 (1.04-1.39) TT 408 (22) 384 (17)  15 (12-17)1.59 (1.33-1.90) 1.32 (1.09-1.59) Additive (47) (41)  7 (6-8) 1.27(1.16-1.38) 1.16 (1.05-1.27) rs2036914 F11 C TT 302 (17) 505 (23)reference   1 (reference)   1 (reference) TC 895 (49) 1081 (49)   7(5-9) 1.38 (1.17-1.64) 1.27 (1.07-1.51) CC 633 (35) 620 (28)  14 (12-16)1.71 (1.43-2.05) 1.43 (1.19-1.73) Additive (59) (53)  7 (6-8) 1.30(1.19-1.42) 1.19 (1.08-1.30) rs4253418 F11 G AA  3 (0)  4 (0) reference  1 (reference)   1 (reference) AG 120 (7) 199 (9)  14 (10-19) 0.80(0.18-3.65) 0.69 (0.15-3.14) GG 1710 (93)  2000 (91)   22 (18-26) 1.14(0.26-5.10) 0.88 (0.20-3.94) Additive (97) (95)  8 (5-11) 1.39(1.11-1.74) 1.24 (0.99-1.56) rs3756011 F11 A CC 361 (26) 598 (34)reference   1 (reference)   1 (reference) CA 697 (50) 839 (48)  8 (7-10)1.38 (1.17-1.62) 1.26 (1.07-1.49) AA 326 (24) 313 (18)  17 (15-20) 1.73(1.41-2.11) 1.44 (0.16-1.78) Additive (49) (42)  9 (7-10) 1.32(1.19-1.46) 1.21 (1.09-1.34) rs3822057 F11 C CC 406 (30) 422 (24)reference   1 (reference)   1 (reference) CA 690 (51) 876 (50)  −8(−10-−5) 0.82 (0.69-0.97) 0.89 (0.75-1.06) AA 269 (20) 457 (26) −14(−16-−11) 0.61 (0.50-0.75) 0.72 (0.58-0.88) Additive (45) (51)  −7(−8-−6) 0.78 (0.71-0.87) 0.85 (0.76-0.94) Abbreviations: CI, confidence1 interval; LETS, Leiden Thrombophilia Study; MEGA, MultipleEnvironmental and Genetic Assessment of Risk Factors for VenousThrombosis; NA, not applicable, not in false discovery rate analysis;OR, odds ratio; SNP, single nucleotide polymorphism. ^(a)Factor XI levelper genotype was calculated in controls. A Factor XI analysis with 95%CI not crossing zero is considered significant. ^(b)OR for DVT, adjustedfor factor XI level. ^(c)As there were no homozygous controls for the Callele of rs3736456, the CT genotype was taken as reference group forthe factor XI difference and genotype OR. For OR results, an analysiswith 95% CI not crossing 1 is considered significant.For rs4253529 (KLKB1), an exemplary genomic context sequence is providedin the Sequence Listing as SEQ ID NO:2557. Note that the allelespresented in Table 8 for rs4253529 are based on a different orientation(i.e., the reverse complement) relative to SEQ ID NO:2557. For rs3775302(KLKB1), an exemplary genomic context sequence is provided in theSequence Listing as SEQ ID NO:2558. For the rest of the SNPs in Table 8,SEQ ID NOs of exemplary sequences are indicated in Tables 1-2.

Example Two Association Between F9 Malmö and Deep Vein Thrombosis

Introduction

In LETS, elevated levels of factor IX above the 90^(th) percentile (129U/dL) have been associated with a 2-3 fold increased risk of DVT (vanHylckama Vlieg et al., Blood. 2000; 95:3678-3682). A genome-wide scanwas recently performed for novel genetic polymorphisms associated withrisk of DVT, as described above in Example One. One of the SNPsidentified was an A-G polymorphism (rs6048, F9 “Malmö”) in the geneencoding Factor IX and was associated with an 18% decrease in DVT riskin 3 case-control studies of DVT. This common variant (minor allelefrequency=0.32) causes a substitution of Ala for Thr at position 148 ofthe factor IX zymogen and is located within the region that is cleavedfrom the zymogen to activate the factor IX protease and has not beenpreviously associated with risk for DVT or hemophilia B (Graham et al.,Am J Hum Genet. 1988; 42:573-580). Thus, the mechanism by which the F9Malmö SNP leads to reduced risk of DVT is unclear.

In the study described here in Example Two, it was determined whetherthe association between the F9 Malmö SNP and DVT could be explained bythe Malmö SNP affecting thrombin generation, Factor IX plasma levels, oractivation of Factor IX. It was also determined whether the associationbetween the F9 Malmö SNP and DVT could be explained by linkagedisequilibrium between the Malmö SNP and other factor IX variants.

Methods

Study Populations and Data Collection

The case-control populations (LETS, MEGA-1 and MEGA-2) used to analyzethe association of genotypes with DVT are derived from two largepopulation-based case-control studies; the Leiden Thrombophilia Study(LETS) and the Multiple Environmental and Genetic Assessment (MEGA) ofrisk factors for venous thrombosis study (van der Meer et al., ThrombHaemost. 1997; 78:631-635; Blom et al., JAMA. 2005; 293:715-722). TheLETS and MEGA studies were approved by the Medical Ethics Committee ofthe Leiden University Medical Center, Leiden, The Netherlands. Allparticipants gave informed consent to participate in the studies,completed a questionnaire on risk factors for venous thrombosis andprovided a blood or buccal swab sample. Diagnoses were objectivelyconfirmed using hospital discharge records and information from generalpractitioners. LETS included only those patients with an confirmed DVT.In MEGA, 90% of patients gave permission to view their medical recordsand within this group 97% of diagnoses were confirmed. Patients for whomDVT was excluded according to the medical record were excluded from theMEGA study. Samples from the Northwick Park Heart Study-II (NPHS-II),were used to evaluate the association of F9 cleavage peptide and withthe Malmö genotypes (Miller et al., Thromb Haemost. 1996; 75:767-771).

Collection and ascertainment of events in LETS has been describedpreviously (van der Meer et al., Thromb Haemost. 1997; 78:631-635).Briefly, cases were recruited between Jan. 1, 1988 and Dec. 30, 1992from three anticoagulation clinics in the western part of theNetherlands: Leiden, Amsterdam, and Rotterdam. A total of 474consecutive cases, 70 years or younger, with a diagnosis of a first DVTand without a known malignancy were included. For each case, an age—(±5years) and sex-matched control participant who had no history of DVT wasenrolled. In this study of LETS, 52 participants were excluded due toinadequate quantity or quality of DNA. After these exclusions, 443 casesand 453 controls remained.

Collection and ascertainment of events in MEGA has been describedpreviously (Blom et al., JAMA. 2005; 293:715-722). Briefly, MEGA-1enrolled consecutive patients aged 18 to 70 years who presented withtheir first diagnosis of DVT or pulmonary embolism (PE) at any of 6anticoagulation clinics in the Netherlands (Amsterdam, Amersfoort, TheHague, Leiden, Rotterdam, and Utrecht) between Mar. 1, 1999 and May 31,2004. Control subjects in MEGA included partners of patients and randompopulation control subjects and were selected so that the distributionof age and sex matched that of the patient group. The first 4,500 MEGAparticipants who donated a blood sample were included in the MEGA-1study. MEGA-1 participants with inadequate quantity or quality of DNA(n=370), malignancy (n=272), or a diagnosis of isolated PE (n=711) wereexcluded. After these exclusions, 1,398 cases and 1,785 controlsremained in the MEGA-1 population. An additional 5,673 MEGA participantsthat donated either a blood sample or a buccal swab sample were includedin the MEGA-2 study. MEGA-2 participants were excluded from the analysisif they had inadequate quantity or quality of DNA (n=467), malignancy(n=433), or a diagnosis of isolated PE (n=639). After these exclusions,1,314 cases and 2,877 controls remained in the MEGA-2 study.

The Northwick Park Heart Study-II (NPHS-II) has been describedpreviously (Miller et al., Thromb Haemost. 1996; 75:767-771). Briefly,4600 men aged 50-63 years registered with 9 general medical practices inEngland and Scotland were screened for eligibility in the NPHS-II.Exclusion criteria for the original study included: a history ofunstable angina or acute myocardial infarction (AMI); a major Q wave onthe electrocardiogram (ECG); regular anti-platelet or anticoagulanttherapy; cerebrovascular disease; life-threatening malignancy;conditions exposing staff to risk or precluding informed consent. Ofthese, 796 men gave written informed consent, were approved by theinstitutional ethics committee and had measurements of F9 cleavagepeptide at baseline.

Allele Frequency and Genotype Determination

DNA concentrations were standardized to 10 ng/μL using PicoGreen(Molecular Probes, Invitrogen Corp, Carlsbad, Calif.) fluorescent dye.Genotyping of individual DNA samples was performed as previouslydescribed in Example One using 0.3 ng of DNA in kPCR assays or usingmultiplexed oligo ligation assays (OLA) (Iannone et al., Cytometry.2000; 39:131-140). Genotyping accuracy of the multiplex methodology andkPCR has been assessed in three previous studies by comparing genotypecalls from multiplex OLA assays with those from real time kPCR assaysfor the same SNPs, and the overall concordance of the genotype callsfrom these two methods was >99% in each of these studies (Iakoubova etal., Arterioscler Thromb Vasc Biol. 2006; 26:2763-2768; Shiffman et al.,Arterioscler Thromb Vasc Biol. 2006; 26:1613-1618; and Shiffman et al.,Am J Hum Genet. 2005; 77:596-605).

Statistical Analysis

Deviations from Hardy-Weinberg expectations were assessed using an exacttest in controls (Weir, Genetic Data Analysis II. Sunderland: SinauerAssociates Inc.; 1996). Adjustments for covariates (age in years andsex) were performed using logistic regression analysis with thegenotypes coded as 0, 1 and 2 for the non-risk homozygote, heterozygote,and risk homozygote, respectively. Logistic regression models wereperformed to assess the association of each genotype (heterozygote andrisk homozygote coded as 2 indicator variables) with the outcome. All Pvalues of statistical tests in LETS and MEGA-1 were two-sided. Analysesof SNPs were conducted separately in males and females since the SNPwere on the X chromosome. SAS version 9 was used for all regressionmodels.

Odds ratios (OR) and 95% confidence intervals (95% CI) were computed asan estimate of risk of DVT associated with each tag SNP in males usinglogistic regression with adjustments for age as previously described.For the allelic OR the major allele homozygote was used as referencegroup. Differences in the factor IX level between genotype categorieswere assessed in control subjects of LETS, MEGA-1 and MEGA-2 using aT-test. Subjects with oral anticoagulant were excluded. Factor IX levelwere available for 191 male and 261 female subjects in LETS, 829 maleand 916 female subjects in MEGA1, 484 male and 2534 female subjects inMEGA2. Among 796 men that had measurements of F9 cleavage peptide atbaseline in NPHS-II, the differences in factor IX cleavage peptidebetween genotype categories were assessed in NPHS-II using a T-test.Regression analyses and T-tests were performed with SAS. Regression inthe NPHS-II was adjusted for age, levels of fibrinogen and creatinine.

Power to detect a difference in mean F9 cleavage peptide between groupsdefined by F9 genotype was calculated using nQuery Advisor version 4.0(ref) for a two sample t-test at a 0.05 two-sided significance level andassuming equal variance among the groups (Elashoff, nQuery AdvisorVersion 4.0 User's Guide. Los Angeles, Calif. (2000)).

Meta analysis was performed using the meta package version 0.8-2available in R software language version 2.4.1 (R: A Language andEnvironment for Statistical Computing, R Development Core Team, RFoundation for Statistical Computing, Vienna Australia, 2007, ISBN3-900051-07-0) by treating the individual studies as fixed effects andusing the inverse variance method to estimate the pooled effect of theSNP (Cooper et al., The Handbook of Research Synthesis. Newbury Park,Calif.: Russell Sage Foundation (1994)).

Gene Variants and DVT Risk in the F9 Region

To investigate whether other SNPs in this region might be associatedwith DVT, results from the HapMap Project were used to identify a regionsurrounding the Malmö SNP, rs6048 (chr X: 138,404,951 to 138,494,063).This region contained 48 SNPs with allele frequencies>2% (HapMap datarelease #221, phase II April 7, on NCBI B36 assembly, dbSNP 126 (Bertinaet al., Pathophysiol Haemost Thromb. 2003; 33:395-400). Allelefrequencies and LD were calculated from the SNP genotypes in the HapMapCEPH population, which includes Utah residents with ancestry fromnorthern and western Europe. Eighteen SNPs were chosen using pairwisetagging in Tagger (implemented in Haploview (Schaid et al., Am J HumGenet. 2002; 70:425-434)). 15 of these 18 SNPs were selected forgenotyping. These 15 SNPs are reasonable surrogates for 45 of the 48SNPs in this region because the 45 SNPs are either directly genotyped orin strong linkage disequilibrium (r²>0.8) with at least one of the 48genotyped SNPs. Assays for 3 of the 18 SNPs could not be constructed(rs4149754, rs438601, and rs17340148); these 3 SNPs are unlikely to beresponsible for the observed association between rs6048 and DVT sincethey were not in strong LD (r²<0.2) with rs6048. The remaining 14 of the48 SNPs were candidates SNPs (Khachidze, Seattle SNPs db, Psaty JAMA).In total 29 SNPs were initially investigated in the males of LETS, andSNPs that were associated with DVT were investigated in the males ofMEGA-1. The association between each genotype and DVT was assessed usingthe Fisher Exact method.

The association between haplotype and DVT was assessed using the Rlanguage package of haplo.stats (Schaid et al., Am J Hum Genet. 2002;70:425-434), which uses the expectation maximization algorithm toestimate haplotype frequencies followed by testing for associationbetween haplotype and disease using a score test. A sliding window wasused to select and test haplotypes consisting of 3, 5, and 7 adjacentSNPs from the set of SNPs including the Malmö SNP and the 28 othertagging SNPs in male subjects.

Factor IX assays

The levels of factor IX were determined by enzyme-linked immunosorbentassay (ELISA) as previously described (van Hylckama Vlieg et al., Blood.2000; 95:3678-3682). This ELISA is highly specific for Factor IX andresults are not affected by the levels of the other vitamin K-dependentproteins. Under these conditions, the intra-assay and interassay CV was7% (n 5 9) and 7.2% (n 5 41), respectively, at a factor IX antigen levelof about 100 U/dL. Results are expressed in units per deciliter, where 1U is the amount of factor IX present in 1 mL pooled normal plasma.

F9 Cleavage Peptide in NPHS-II

F9 cleavage peptide was determined by double antibody radioimmunoassayas markers of turnover of Factor IX in the NPHS-II samples (Bauer etal., Blood. 1990; 76:731-736). The coefficient of variation (CV) formeasurements made during repeat measurements on split samples were 14.7%for Factor IX cleavage peptide. The level of cleavage peptide in plasmais dependent on Factor IX levels, which are affected by age andinflammation, and on kidney function. The effects of inflammation andkidney function were assessed by adjusting the analysis for the levelsof fibrinogen and creatinine, respectively.

Endogenous Thrombin Potential (ETP)-Based APC Sensitivity Test

Endogenous thrombin potential (ETP) is an activate protein C (APC)sensitivity test that quantifies the time integral of thrombin generatedin plasma in which coagulation is initiated via the extrinsic pathway(Hemker et al., Thromb Haemost. 1995; 74:134-138 and Nicolaes et al.,Blood Coagul Fibrinolysis. 1997; 8:28-38). The sensitivity of the plasmaETP to APC was measured under conditions where the test is insensitivefor small amounts of phospholipid present in plasma as previouslydescribed (Rosing et al., Br J Haematol. 1997; 97:233-238; Tans et al.,Br J Haematol. 2003; 122:465-470; and Curvers et al., Thromb Haemost.2002; 87:483-492).

Results

The Malmö SNP was previously found to be associated with DVT in men andnot in women. In the previous analysis, women that were heterozygoticfor the Malmo SNP were excluded from the analysis because lyonization,the process in which all X chromosomes of the cells in excess of one areinactivated on a random basis, causes the expressed genotypes to bedifferent from the determined genotypes. Removing the heterozygote inthe analysis in women reduces the power to detect associations betweengenotypes and DVT in women, which could explain why the association ofMalmo with DVT in women had an OR for DVT that was similar to that foundin men, but was not significant. It was found that the Malmö SNP,rs6048, was associated with DVT in men:the pooled odds ratio was 0.80(95% CI, 0.71-0.92) for the A genotype (n=2688) compared with G(n=1108), but the Malmö SNP was not associated with DVT in women:thepooled odds ratio was 0.86 (95% CI, 0.70-0.1.05) for the AA (n=2190)compared with GG genotypes (n=405) (FIG. 2). Thus, analyses for thisstudy were done in men.

It was determined whether the association between the F9 Malmö SNP andDVT could be explained by an association between the Malmö SNP andendogenous thrombin potential (ETP). Among the 161 male subjects of LETSfor whom ETP measurements were available, it was found that Malmögenotype was not associated with ETP (median ETP=1657±341 for the Agenotype and 1583±361 for the G genotype).

It was determined whether the association between the F9 Malmö SNP andDVT could be explained by an association between the Malmö SNP andFactor IX plasma levels. Among the male subjects for whom Factor IXplasma levels were available (161 in LETS, 829 in MEGA1 and 484 inMEGA2), there was not a significant difference in Factor IX levelbetween the A and the G genotype. For the LETS subjects the mean FIXlevels were 104±17% for the A genotype and 109±24% for the G genotype,P=0.0965. For the MEGA-1 subjects the mean Factor IX levels were 104±17%for patients with genotype A and 102±18% for the G genotype, P=0.119.For the MEGA-2 subjects the mean Factor IX levels were 104±15% for thegenotype A and 104±18% for the G genotype, P=1.0).

It was determined whether the association between the F9 Malmö SNP andDVT could be explained by an association between the Malmö SNP andactivation of Factor IX. Among the 796 male subjects of NPHS-II for whomplasma F9 cleavage peptide levels were available, there was not asignificant difference in Factor IX level between the A and G genotypes;the mean plasma concentration of F9 cleavage peptide was 210.9+−75.04(95% Cl: 204.6 to 217.2) for A genotype and 214.1+−73.82 (95% Cl: 204.7to 223.4) for the G genotype. Adjustments for age, fibrinogen andcreatinine levels did not appreciably change this result. The study had80% power to detect a difference in means of 0.22 standard deviations orgreater, or 90% power to detect a difference in means of 0.25 standarddeviations or greater.

It was then determined whether the Malmö SNP was in linkagedisequilibrium (LD) with other F9 variants that were associated withDVT. In the LETS population, 29 SNPs were investigated that representedgroups of SNPs with LD greater than 0.8 in an 89 kb region surroundingthe Malmö SNP on the X chromosome. It was found that six of the 29 SNPs,including the Malmö SNP, were associated (P≦0.05) with DVT (Table 9).The association between these six SNPs and DVT were then investigated inthe MEGA-1 study, and two of these SNPs were found to be significantlyassociated with DVT in MEGA-1: the Malmö SNP and rs422187, an intronicSNP 300 bp from the Malmö SNP (Table 9). The risk estimate for theassociation between rs422187 and DVT was similar to that of the MalmöSNP, and LD between rs422187 and the Malmö SNP was high (r²=0.94).Additionally, no SNPs or haplotypes were found to have a strongerassociation with DVT in the LETS or MEGA studies than the F9 Malmö SNP.

Discussion

It was investigated whether the previously reported association betweenDVT and the F9 Malmö SNP could be explained by changes in plasma levelsof Factor IX, extrinsic coagulation, Factor IX activation, or LD withSNPs with stronger association with DVT than the Malmö SNP. However,analyses to directly or indirectly test these hypotheses did not providesupport for any of them. Although the Malmö SNP did not affect ETP, anassay that measures extrinsic pathway coagulation initiated by TF:FVIIa,the Malmö SNP could have an affect on coagulation initiated by intrinsicpathway coagulation initiated by FXIa. The lack of an association of theMalmö SNP with Factor IX levels is consistent with the results ofKhadhidze et al, which reported that 27 SNPs including F9 Malmö were notassociated with FIX:C in the GAIT study (Khachidze et al., J ThrombHaemost. 2006; 4:1537-1545). The analysis of activation described herein Example Two used an indirect assay to estimate activation of FactorIX. The plasma level of the F9 cleavage peptide is dependent on therelease of cleavage peptide that occurs when FIX is activated to FIXaand the steady clearance rate of the cleavage peptide in the kidneys(Lowe, Br J Haematol. 2001; 115:507-513). Direct measurements of FactorIX activation by TF:FVIIA or FXIa may reveal affects on the activationof Factor IX caused by F9 Malmö SNP.

The association of the Malmö SNP with DVT was previously reported in menas described in Example One. The result was not significant in womenalthough the odds ratio in women was similar to that found in men. TheLETS, MEGA-1 and MEGA-2 samples were pooled because these samples werecollected in the Netherlands in the same health care system usingsimilar inclusion criteria. The LETS inclusion and exclusion criteriawere applied to the MEGA samples and they were pooled for meta-analysis.In the meta-analysis, the Malmö SNP was associated with DVT in men butwas not with women although the odds ratio for men and women weresimilar. In the analysis of women, the AA genotype was compared with theGG genotype. However, the heterozygotes were excluded from the analysisbecause evaluation of female heterozygotes is confounded by lyonization.Therefore, the lack of association in female could be due to differencesin penetrance between men and women or lack of power to detect theassociation in female homozygotes. The lack of an association betweenthe Malmö SNP and DVT in women is consistent with recent resultsobserved in postmenopausal women (Smith et al., JAMA. 2007;297:489-498).

Fine mapping did not identify any SNPs that were more stronglyassociated with DVT than the Malmö SNP in the LETS and MEGA-1 samples. Arecent study found that rs4149755 in the F9 gene was associated with DVTin postmenopausal women (Smith et al., JAMA. 2007; 297:489-498).rs4149755 was included in the fine mapping analysis in LETS, butrs4149755 was not associated with DVT in men (Table 9) or in women. Nohaplotypes were found using the evaluated fine mapping SNPs that weremore strongly associated with DVT in both LETS and MEGA-1.

In conclusion, the Malmö SNP in F9 was significantly associated with an18% reduction in risk of DVT in a pooled analysis of men from LETS,MEGA-1 and MEGA-2. Fine mapping of the F9 region surrounding the MalmöSNP did not reveal any additional SNPs associated with DVT in LETS andMEGA-1 or SNPs with greater significance than the Malmö SNP.

TABLE 9 The F9 MalmöP0 SNP fine mapping results in LETS and MEGA-1 MinorP- r² with X Chromosome Study Allele MAF Value OR Malmö rs# Position SNPType LETS A 0.32 0.088 0.67 0.40 rs4829996 138418800 Intergenic LETS G0.08 0.849 0.92 0.02 rs7055668(T) 138427049 Intergenic LETS A 0.39 0.0670.66 0.26 rs411017 138439768 Intergenic LETS T 0.39 0.068 0.67 0.26rs378815(T) 138439863 TFBS synonymous LETS G 0.02 1.000 0.67 0.01rs3817939(T) 138440752 TFBS synonymous LETS C 0.44 0.538 1.14 0.06rs371000(T) 138443187 TFBS synonymous LETS T 0.38 0.190 0.74 0.65rs4149674(T) 138444467 Intron LETS T 0.08 1.000 1.07 0.03 rs392959(T)138449920 Intron LETS G 0.34 0.032 0.61 0.85 rs398101 138451623 IntronLETS A 0.06 0.423 1.42 0.03 rs4149755 138451778 Intron LETS A 0.08 0.5430.73 0.18 rs4149758 138455143 Intron LETS G 0.07 1.000 1.00 0.02rs374988(T) 138458881 Intron LETS C 0.33 0.039 0.61 0.94 rs422187138460525 Intron MEGA-1 C 0.32 0.016 0.88 0.93 LETS G 0.33 0.022 0.58 NArs6048(T) 138460946 Missense Mutation MEGA-1 G 0.30 0.021 0.88 NA LETS C0.09 0.454 0.74 0.08 rs4149759(T) 138462720 Intron LETS G 0.24 0.0410.58 0.44 rs413957 138465182 Intron LETS T 0.01 0.248 N/A 0.01rs4149761(T) 138467129 Intron LETS T 0.03 1.000 0.99 0.02 rs4149730(T)138467398 Intron LETS C 0.24 0.029 0.56 0.45 rs421766 138468258Intron/TFBS LETS A 0.05 0.230 1.76 0.00 rs4149762(T) 138469863 IntronLETS C 0.25 0.041 0.57 0.45 rs370713 138470059 Intron LETS T 0.00 1.000N/A 0.00 rs4149749 138470891 Intron/TFBS LETS A 0.00 1.000 N/A 0.00rs4149763 138472372 UTR3 LETS A 0.24 0.057 0.61 0.43 rs440051(T)138472583 TFBS/UTR3 LETS G 0.26 0.008 0.50 0.42 rs434144 138474091Intergenic LETS A 0.01 0.247 N/A 0.00 rs17342358(T) 138482244 TFBSsynonymous LETS T 0.45 0.411 1.21 0.00 rs5907573(T) 138489652 TFBS LETSC 0.44 0.305 1.26 0.00 rs3128282 138490821 Intergenic LETS A 0.01 0.499N/A 0.00 rs2235708 138506410 ESE (T) = tagging SNP; MAF = minor allelefrequency TFBS = Transcription Factor Binding Site; ESE = exon splicingenhancer N/A = Not applicable or the calculation contained a group withzero counts. Unadjusted allelic odds ratios and P-values were calculatedby the Fisher Exact method in men. 15/18 tag SNPs were run in LETS, 3single SNP tags were not run in LETS

Example Three Gene Variants of Cyp4V2, SERPINC1 and GP6 are Associatedwith Pulmonary Embolism

Overview

Pulmonary embolism (PE) is a manifestation of venous thrombosis (VT)that may share genetic risk factors in common with deep vein thrombosis(DVT). To identify SNPs associated with isolated PE, 11 SNPs previouslyfound to be associated with DVT were analyzed for their association withisolated PE in a case-control study of 1206 cases and 4634 controls fromthe Multiple Environmental and Genetic Assessment (MEGA) study. Oddsratios (OR) for isolated PE were estimated in logistic regression modelsthat adjusted for age and sex.

SNPs determined to be associated with isolated PE included SNPs in genesfor CYP4V2 (rs13146272: OR, 1.15; 95% CI, 1.04-1.27), GP6 (rs1613662:OR, 1.18; 95% CI, 1.04-1.33) and SERPINC1 (rs2227589: OR, 1.28; 95% CI,1.11-1.48) and F9 in females (rs6048: OR, 1.20; 95% CI, 1.06-1.38). Manyof these SNPs were found in genes not previously reported to be involvedin VT. Factor V Leiden and prothrombin G20210A variants were associatedwith isolated DVT (rs6025: OR, 4.43; 95% CI, 3.76-5.22; rs1799963: OR,3.01; 95% CI, 2.29-3.95) and with isolated PE (rs6025: OR, 1.82; 95% CI,1.45-2.28; rs1799963: OR, 1.82; 95% CI, 1.27-2.62); however, the casefrequencies were significantly lower in the isolated PE study comparedto the isolated DVT study (P<0.01).

Introduction

Pulmonary embolism (PE) is a common and potentially fatal manifestationof VT, which occurs as a consequence of a DVT that embolizes to thelung. VT affects about 750,000 patients annually in the EU and about600,000 patients annually in the US. It is the 3^(rd) most commoncardiovascular disease worldwide, behind CHD and stroke (Zidane et. al.,Throm Haemost 2003 90:439-445 and Perrier, Chest 200 118:1234-6)

In the United States, the total incidence of symptomatic PE isapproximately 630,000 cases per year. Approximately a third of thesepatients die, and in nearly half of these patients who die, PE is thesole cause of death (Diseases of the Veins. Pathology, diagnosis andtreatment. In: Browse et al., editors. Pulmonary embolism.London:Edwards Arnolds; 1989. p 557-80). Estimates of the total numberof non-fatal PE event across Europe exceed 400,000 per year and thetotal number of PE-related deaths is about 514,000 (Cohen, ThrombHaemost (2007) 98, 756-764 and Lindblad, B M J 1991; 302; 709-711). PEis the major cause of VT deaths.

The genetic risk factors for PE may be different for DVT. It has beenassumed that PE and DVT share the same genetic risk factors. However,studies that evaluated the factor V Leiden (FVL) variant (which is knownto be associated with DVT) in patients with PE but without DVT foundthat it was weakly associated with PE. In addition, genetic variants maypredispose the thrombus to particular vascular beds. For example,patients with PT G20210A mutations are predisposed to portal veinthrombosis whereas individuals with FVL variants are not, and it hasbeen suggested that patient with FVL are predisposed to DVTs of thecalf. Thus, although DVT and PE may be different manifestations of thesame disease, they may not share all the same risk factors.

A functional genome-wide scan of DVT was recently performed and sevenSNPs were identified that were associated with DVT in threecase-controls studies, as described in Example One above. Here inExample Three, it was determined whether any of these seven SNPs, plusfour other SNPs (in F2, F5, and F11), were also associated with isolatedPE.

Methods

Study Populations and Data Collection

This genetic study of PE investigated patients with PE selected from theMultiple Environmental and Genetic Assessment of risk factors for venousthrombosis (MEGA) study (Blom et al., JAMA. Feb. 9, 2005;293(6):715-722). The MEGA study was approved by the Medical EthicsCommittee of the Leiden University Medical Center, Leiden, TheNetherlands. All participants gave informed consent to participate inthe studies and completed an institutional review board-approvedquestionnaire. Diagnoses of PE and DVT in the studies were objectivelyconfirmed using hospital discharge records and information from generalpractitioners. Patients with isolated PE had a confirmed PE and norecord of a DVT, and patients with isolated DVT had a confirmed DVT andno record of a PE.

The Multiple Environmental and Genetic Assessment Study (MEGA)

Collection and ascertainment of events in MEGA has been describedpreviously (Blom et al., JAMA. Feb. 9, 2005; 293(6):715-722). MEGAenrolled consecutive patients aged 18 to 70 years who presented withtheir first diagnosis of DVT or PE at any of 6 anticoagulation clinicsin the Netherlands (Amsterdam, Amersfoort, The Hague, Leiden, Rotterdam,and Utrecht) between Mar. 1, 1999 and May 31, 2004. The anticoagulationclinics monitor the anticoagulant therapy of all patients in definedregions of the Netherlands, which allowed them to identify consecutiveand unselected cases with DVT. Partners of cases were invited to takepart as controls. Additional control participants were recruited byrandom digit dialing from the same region that the cases were collected(Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592).The age and sex of the controls were matched to cases. MEGA DNA wascollected and extracted from blood or buccal swabs as previouslydescribed (Blom et al., JAMA. Feb. 9, 2005; 293(6):715-722). MEGAincluded ˜10,000 participants. Subjects were excluded due to inadequatequantity or quality of DNA (n=370+467), for malignancy (n=272+433).

Allele Frequency and Genotype Determination

Genotypes were determined by kPCR or multiplex oligo-ligation assay. DNAconcentrations were standardized to 10 ng/μL using PicoGreen (MolecularProbes) fluorescent dye. Each allele was amplified separately by PCRusing genotyping of individual DNA samples was similarly performed using0.3 ng of DNA in kinetic polymerase chain reaction (kPCR) assays (Germeret al., Genome Res. February 2000; 10(2):258-266) or using multiplex PCRassays capable of genotyping up to 50 SNPs in a single reaction (Tannoneet al., Cytometry. Feb. 1, 2000; 39(2):131-140). Genotyping accuracy ofthe multiplex methodology has been assessed in three previous studies bycomparing genotype calls from the multiplex OLA assays to those fromreal time kinetic PCR assays for the same SNPs, and the overallconcordance of the genotype calls from these two methods was >99% ineach of these studies (Iakoubova et al., Arterioscler Thromb Vasc Biol.Sep. 28, 2006; 26(26):2763-2768; Shiffman et al., Arterioscler ThrombVasc Biol. July 2006; 26(7):1613-1618; and Shiffman et al., Am J HumGenet. October 2005; 77(4):596-605). The 7 assays associated with DVT inMEGA were successfully genotyped in >95% of the subjects in MEGA.

Study Design

To identify genetic risk variants that were associated with isolated PE,the risk allele of 11 SNPs previously associated with DVT were evaluatedfor their association with isolated PE in MEGA. The case-control studiesof DVT that were used to identify 7 of these SNPs (out of the 11 SNPs)excluded patient with isolated PE. This study evaluates these patientswith isolated PE who were excluded from the studies used to identifythese SNPs. The same controls used in the DVT discovery studies wereused for this study. The controls were subjects with no history of VT.

Study Populations

The baseline characteristics of the cases and controls in the isolatedPE and isolated DVT studies of MEGA are presented in Table 10.

Statistical Analysis

Deviations from Hardy-Weinberg expectations were assessed using an exacttest in controls (Weir, Genetic Data Analysis 2: Methods for DiscretePopulation Genetic Data 2nd edition (April 1996) ed. Sunderland: SinauerAssociates; 1996). Adjustments for covariates (age in years, and sex)were performed using logistic regression analysis with the genotypescoded as 0, 1 and 2 for the non-risk homozygote, heterozygote, and riskhomozygote, respectively. For the SNPs presented in Table 11, logisticregression models were performed to assess the association of eachgenotype (heterozygote and risk homozygote coded as 2 indicatorvariables) with the outcome. All statistical tests in MEGA weretwo-sided.

Results

SNPs Associated with PE in MEGA

In MEGA, the association with isolated PE of 7 SNPs previously found tobe associated with DVT was analyzed. In the controls of MEGA, thegenotypes of the 11 SNPs did not deviate from the distributions expectedunder Hardy-Weinberg equilibrium (P≦0.01) (Weir, Genetic Data Analysis2: Methods for Discrete Population Genetic Data 2nd edition (April 1996)ed. Sunderland: Sinauer Associates; 1996). The method of Bonferoni wasused to correct for multiple comparisons. Both the isolated DVT andisolated PE studies of MEGA had greater than 80% to detect associationof the 7 SNP (power=0.5 for 0.1 allele frequency)

Eight of the 11 SNPs evaluated were associated (P≦0.05) with isolatedPE. These were in the genes for CYP4V2, GP6, SERPINC1, F2, F5, and F11.The risk allele and OR of these SNPs can be found in Table 11. Theassociations between isolated PE and each genotype of these eightassociated SNPs are shown in Table 12.

Six of the 11 SNPs evaluated were associated (P≦0.05) with isolated DVT.These were in the genes for CYP4V2, GP6, SERPINC1, RGS7, NRI12, andNAT8. The associations between isolated DVT and each genotype of theseSNPs are shown in Table 13.

The case allele frequencies for FVL and PT are substantially lower(P<0.05) in the case frequencies of the isolated DVT study than in theisolated PE study, which is reflected as a lower risk estimates for FVLand PT in the isolated PE study than in the isolated DVT study. Thethree SNPs in genes for NRI12, NAT8 and RGS7 that were associated withisolated DVT but not with isolated PE, also have slightly lower casefrequencies in the isolated DVT study compared to the isolated PE study,although the frequency differences were not statistically significant.

Discussion

Eight SNPs in genes for CYP4V2, SERPINC1, GP6, F2, F5, and F11 (Table12) were identified that were associated with isolated PE in a large,well characterized case-control population (MEGA) (1206 PE cases and4634 controls). The associations were corrected for multiple testingusing the Bonferroni method. The risk alleles associated with isolatedPE for each of the SNPs are the same risk alleles previously reported tobe associated with DVT, as described in Example One.

This study also confirmed that established genetic risk factors forvenous thrombosis, notably FVL (Chinthammitr et al., J Thromb Haemost.December 2006; 4(12):2587-2592 and Bertina et al., Nature. May 5, 1994;369(6475):64-67) and prothrombin G20210A (Chinthammitr et al., J ThrombHaemost. December 2006; 4(12):2587-2592 and Poort et al., Blood. Nov.15, 1996; 88(10):3698-3703), are associated with isolated PE in MEGA.However, the risk estimates for FVL and prothrombin G20210A withisolated PE are about half of the risk estimated found for isolated DVT(FVL, OR=4.43 and OR=1.82, respectively; PT, OR=3.01 and OR=1.82)(Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592and Poort et al., Blood. Nov. 15, 1996; 88(10):3698-3703).

These results are consistent with the previous associations of FVL andPT with isolated DVT and isolated PE. The most notable of the geneticrisk factors for DVT is Factor V Leiden, which has an OR for DVT of 6.Intriguingly, studies of consecutive suspected PE patients found thatthere was no difference in the prevalence of FVL in patients with orwith out confirmed PE. This was been replicated in many other studies(Perrier, Chest 200 118:1234-6). This weak association of FVL with PE isin sharp contrast to its association with DVT and has been called theFactor V Leiden paradox. It has been suggested that the reason for thisparadox is that DVT patients with FVL are more likely to have a distalDVT which is less likely to embolize (i.e., lower tendency to developiliofemoral DVT that carriers). However, this was not substantiated byMartinelli (JTH 5: 98-101). The paradox suggests that although FVL is animportant risk factor for DVT, it may not increase the risk of PE. SincePE cause most VT deaths and is therefore more clinically important thanDVT (Martinelli, JTH 5:98-101), it has been suggested that patient withFVL should be treated less aggressively rather than more aggressively(Bounameaux, Lancet (2000) 356:182-183).

PT G20210A is another genetic risk factor associated with differentmanifestations of VT. PT G20210A is associated with increased portalvein VT, whereas FVL is not (Primignami et al., Heptology 200541:603-8). In addition, some studies suggest that carriers of PT G20210Ahave an increased risk of developing PE, which is similar to that seenfor DVT. PT G20210 has an OR of 3.0 for DVT. However, other studiessuggest that PT G20210A is not associated with risk in PE, which (likeFVL) is not explained by a difference in the rate of distal versusproximal DVT. Unfortunately, these studies are complicated by the lowallele frequency of the PT G20210A variant. One of the advantages of theMEGA study is it large size, which provides greater power for detectingassociations. In the current study, FVL and PT were both found to beassociated with isolated PE and isolated DVT. However, the riskestimates were lower in the isolated PE study than in the isolated DVT,which is consistent with literature reports of FVL and PT not beingassociated with isolated PE in smaller studies having less power.

Although SERPINC1 is located in the same region of chromosome 1 as theFactor V gene, its association with isolated DVT or isolated PE is notdue to linkage-disequilibrium with the FVL variant (see Example One).

Conclusions

Eight SNPs were identified that were associated with isolated PE in theMEGA study. These variants are useful for assessing genetic risk of PE,and the genes containing these variants and the products encoded bythese genes (e.g., protein and mRNA) are useful as therapeutic targetsfor treating PE.

Additional SNPs associated with PE are provided in Table 25 (ExampleSeven below).

TABLE 10 Characteristics of Cases and Controls in MEGA Charac- PE CasesDVT Cases Controls P value teristic n = 1206 n = 2229 n = 4634 DVT* PE⁴⁶Male, % 498 (41.2) (1032) 46.3 (2191) 47.3 0.45 1.7E−0.4 Age, years Mean± 47 (13)  47 (13) 47 (13) 0.46 0.64 SD Range 18.1-70.0 18.2-70.018.0-70.0 Differences between characteristics were assessed by theWilcoxon rank sum test (continuous variables) or by Fisher's exact test(discrete variables). *Comparison between DVT cases and controls.^(†)Comparison between PE cases and controls.

TABLE 11 Association of Nine SNPs with Isolated DVT or PE Gene RiskFrequency (%) Unadjusted Adjusted Symbol SNP Endpoint Allele* CasesControl OR (95% CI) P Value OR (95% CI) P Value CYP4V2 rs13146272 PE A67 64 1.15 (1.05-1.27) 0.004 1.15 (1.04-1.27) 0.005 DVT 68 64 1.19(1.10-1.29) <0.0001 1.19 (1.10-1.29) <0.0001 SERPINC1 rs2227589 PE T 129 1.28 (1.11-1.48) 0.0003 1.28 (1.11-1.48) 0.001 DVT 11 9 1.24(1.10-1.39) 0.0004 1.24 (1.10-1.39) 0.0003 GP6 rs1613662 PE A 84 82 1.18(1.04-1.33) 0.009 1.18 (1.04-1.33) 0.008 DVT 84 82 1.15 (1.04-1.26)0.005 1.15 (1.04-1.33) 0.005 RGS7 rs670659 PE C 65 64 1.03 (0.93-1.13)0.58 1.02 (0.93-1.13) 0.62 DVT 67 64 1.12 (1.04-1.21) 0.003 1.13(1.04-1.21) 0.002 NR1I2 rs1523127 PE C 40 38 1.05 (0.96-1.15) 0.30 1.05(0.96-1.15) 0.30 DVT 41 38 1.12 (1.04-1.21) 0.002 1.12 (1.04-1.21) 0.002NAT8B rs2001490 PE C 37 37 0.99 (0.91-1.09) 0.59 0.99 (0.91-1.09) 0.91DVT 40 37 1.11 (1.03-1.20) 0.005 1.11 (0.91-1.09) 0.005 F9 rs6048 PEMale A 72 69 1.24 (0.99-1.55) 0.06 1.24 (1.00-1.55) 0.06 Female 90 881.21 (1.06-1.38) 0.005 1.20 (1.06-1.38) 0.006 DVT Male A 74 69 1.16(0.99-1.37) 0.07 1.16 (0.98-1.37) 0.08 Female 90 88 1.07 (0.96-1.19)0.20 1.06 (0.95-1.18) 0.29 F2 rs1799963 PE A 2 1 1.85 (1.29-2.66) 0.00091.82 (1.27-2.62) 0.001 DVT 3 1 3.01 (2.30-3.96) <0.0001 3.01 (2.29-3.95)<0.0001 F5 rs6025 PE A 5 3 1.81 (1.45-2.27) <0.0001 1.82 (1.45-2.28)<0.0001 DVT 11 3 4.42 (3.75-5.21) <0.0001 4.43 (3.76-5.22) <0.0001 SNPannotation based on build 126, (human genome map 36) of the NCBI SNPdatabase. The risk estimate was calculated based on the risk alleleanalyzed using the general DVT endpoint. *Allele frequency for the riskallele. ^(†)OR denotes odds ratio, which were estimated and adjusted forage and sex by logistic regression using an additive model. Sex wasincluded as a covariate in logistic regression models containing markersresiding on the X chromosome and the number of risk alleles for theseSNPs were coded as 0 or 1 for males and 0, 1 or 2 for females.

TABLE 12 Association of Eight SNPs with PE Count (Frequency %)Unadjusted Adjusted^(‡) Gene SNP Risk allele Genotype Case Control OR(95% CI) P Value OR (95% CI) P Value SERPINC1 rs2227589 T TT 20 (2)  43(1) 1.87 (1.09-3.20) 0.02 1.85 (1.08-3.16) 0.02 TC 239 (20)  766 (17)1.26 (1.07-1.48) 0.006 1.23 (1.08-1.41) 0.002 CC 940 (78) 3782 (82) RefRef CYP4V2 rs13146272 A AA 513 (45) 1814 (41) 1.35 (1.08-1.68) 0.0081.35 (1.08-1.67) 0.008 AC 494 (44) 1983 (45) 1.19 (0.95-1.48) 0.13 1.18(0.95-1.47) 0.14 CC 122 (11)  581 (13) Ref Ref GP6 rs1613662 A AA 842(71) 3059 (67) 1.29 (0.87-1.90) 0.20 1.30 (0.88-1.92) 0.19 GA 319 (27)1388 (30) 1.08 (0.72-1.61) 0.72 1.08 (0.72-1.62) 0.70 GG 32 (3) 150 (3)Ref Ref F2 rs1799963 A AA  1 (0)  0 (0) — — — — AG 42 (4)  92 (2) 1.78(1.23-2.58) 0.002 1.75 (1.21-2.54) 0.003 GG 1157 (96)  4514 (98) Ref RefF5 rs6025 A AA  4 (0)  7 (0) 2.29 (0.67-7.84) 0.19 2.29 (0.67-7.86) 0.19AG 105 (9)  226 (5) 1.86 (1.46-2.37) <0.0001 1.87 (1.47-2.38) <0.0001 GG1076 (91)  4312 (95) Ref Ref F5 rs4524 T TT 702 (60) 2466 (55) Ref RefCT 410 (35) 1713 (38) 0.84 (0.73-0.96) 0.013 0.84 (0.74-0.97) 0.015 CC58 (5) 325 (7) 0.63 (0.47-0.84) 0.002 0.62 (0.46-0.83) 0.001 F11rs4253418 G GG 1095 (93)  4120 (91) Ref Ref AG 76 (6) 381 (8) 0.75(0.58-0.97) 0.03 0.75 (0.58-0.97) 0.029 AA  5 (0)  11 (0) 1.71(0.59-1.93) 0.32 1.68 (0.58-4.85) 0.338 F11 rs3756008 T AA 368 (31) 1672(37) Ref Ref TA 573 (49) 2115 (47) 1.23 (1.06-1.42) 0.005 1.23(1.07-1.43) 0.005 TT 234 (20)  730 (16) 1.46 (1.21-1.75) <0.001 1.46(1.22-1.76) <0.001 *Genotypic allele frequency. †The risk estimate (oddsratio) was calculated based on the risk allele analyzed with the generalDVT endpoint. ^(‡)Adjusted for age and sex.

TABLE 13 Association of Five SNPs with Isolated DVT Count (Frequency %)Unadjusted Adjusted^(‡) Gene SNP Genotype Case Control OR (95% CI) PValue OR (95% CI) P Value SERPINC1 rs2227589 TT 31 (1)  43 (1) 1.57(0.98-2.50) 0.06 1.57 (0.98-2.49) 0.06 TC 434 (20)  766 (17) 1.23(1.08-1.40) 0.002 1.23 (1.08-1.41) 0.002 CC 1740 (79)  3782 (82) Ref RefCYP4V2 rs13146272 AA 991 (47) 1814 (41) 1.37 (1.15-1.62) 0.0003 1.37(1.15-1.62) 0.0003 AC 879 (42) 1983 (45) 1.11 (0.94-1.32) 0.23 1.11(0.93-1.32) 0.24 CC 232 (11)  581 (13) Ref Ref GP6 rs1613662 AA 1546(70)  3059 (67) 1.26 (0.93-1.72) 0.13 1.26 (0.93-1.71) 0.13 GA 604 (27)1388 (30) 1.09 (0.80-1.49) 0.60 1.09 (0.79-1.49) 0.60 GG 60 (3) 150 (3)Ref Ref F2 rs1799963 AA  0 (0)  0 (0) — — — — AG 128 (6)   92 (2) 3.01(2.29-3.96) <0.0001 1.75 (1.21-2.54) 0.003 GG 2085 (94)  4514 (98) RefRef F5 rs6025 AA 16 (1)  7 (0) 5.64 (2.32-13.74) 0.0001 2.29 (0.67-7.86)0.19 AG 431 (20) 226 (5) 4.71 (3.97-5.58) <0.0001 1.87 (1.47-2.38)<0.0001 GG 1746 (80)  4312 (95) Ref Ref *Genotypic allele frequency.^(†)The odds ratio was calculated based on the risk allele analyzedusing the general DVT endpoint. ^(‡)Adjusted for age and sex.

Example Four Multiple SNPs Independently Associated with Expression ofFactor XI and Risk of Deep Vein Thrombosis

Overview

Two recent studies have detected association of DVT risk with SNPs inthe 4q35 locus that contains genes encoding cytochrome P450, family 4,subfamily V, polypeptide 2 (CYP4V2), factor XI (F11) and prekallikrein(KLKB1) (Smith et al., JAMA 297, 489-98 (2007) and Bezemer et al., JAMA299, 1306-14 (2008)). To determine the risk gene(s) among thesecandidates and identify the variants most likely to have a functionalrole in altering the risk for DVT, an analysis involving densegenotyping and association testing of 103 SNPs over 200 kbp in theCYP4V2/KLKB1/F11 locus in large case control sample sets (up to 3,155cases and 5,087 controls) was carried out. Disease-SNP modelingidentified three independently risk-related SNPs: rs2289252 (in F11,OR_(homozygote [)95% CI]=1.84 [1.62-2.10], P_(genotypic)=1.7×10⁻²⁰),rs2036914 (in F11: OR_(homozygote [)95% CI]=1.84 [1.61-2.10],P_(genotypic)=6.5×10⁻¹⁹), and rs13146272 (in CYP4 V2, OR_(homozygote)[95% CI]=1.58 [1.29-1.76], P_(genotypic)=2.1×10⁻⁷). Genotypes of thesemarkers are associated with the level of factor XI (FXI) which is knownto associate with DVT (e.g., P=2.1×10⁻²⁰ for rs2289252) (Meijers et al.,N Engl J Med 342, 696-701 (2000)), and carriers of risk genotypes havehigher levels of FXI than non-carriers. These data indicate that SNPs inCYP4V2 and F11 confer risk of DVT that is at least partly explained byFXI levels.

Introduction

In a large scale, gene-centric SNP-based association study,statistically significant associations were found between DVT and SNPsin the CYP4V2 region on chromosome 4, SERPINC1 on chromosome 1, and GP6on chromosome 19 (Bezemer et al., JAMA 299, 1306-14 (2008)), asdescribed above in Example One. Additional genotyping in the CYP4V2region identified several associated markers in the neighboring genes,encoding factor XI (F11) and prekallikrein (KLKB1). In a candidategene-based association study, Smith et al. reported that two SNPs in F11were associated with risk of DVT in postmenopausal women with DVT (Smithet al., JAMA 297, 489-98 (2007)).

However, because of LD and the limited coverage of the genome by theinitial characterizations, it remained undetermined whether the observedmarkers are “causal” or serve as proxies to untested causal variants andwhether other variants at this locus add to DVT risk. Identification ofthe causal variants enables a better assessment of proper effect sizeand further understanding of pertinent biological mechanisms. This is ofparticular interest for the 4q35 region, since F11 and its homologueKLKB1 are both known to be involved in the intrinsic blood coagulationcascade: in the initial contact phase, activation of Factor XII istriggered in the presence of prekallikrein, a serine protease, resultingin subsequent activation of factor XI (FXI) that further leads to themiddle phase of the intrinsic pathway of blood coagulation (Gailani etal., J Thromb Haemost 5, 1106-12 (2007)). Therefore, functional geneticvariants in either F11 or KLKB1 may modulate DVT risk. For example, itis known that high levels of FXI are associated with increased risk ofDVT (Meijers et al., N Engl J Med 342, 696-701 (2000)). To identifycausal markers, an analysis involving comprehensive genotyping andassociation with DVT testing in the CYP4V2/KLKB1/F11 locus was carriedout, which is described here in Example Four.

Results and Discussion

According to the HapMap CEPH dataset, the entire locus containingCYP4V2, KLKB1 and F11 resides in a region of high LD that is distinctfrom adjacent LD regions. To identify the causal marker(s), the regioncontaining these genes was interrogated with 103 SNPs. The majority ofthese markers (90.3%) were selected to cover SNP diversity in theregion. These 103 SNPs were first evaluated in two sample sets thatcontained 2,210 controls and 1,841 DVT cases: The Leiden ThrombophiliaStudy (LETS) and a subset of The Multiple Environmental and GeneticAssessment (MEGA) study, MEGA-1. The allelic association between 54 SNPsand DVT reached a significance level of 0.05; the 7 most significantmarkers were clustered in the F11 gene (Table 17). Two highly correlatedF11 SNPs, rs3756011 and rs2289252 (r²=0.98), showed the strongestassociation with DVT (P=5.2×10⁻⁹ and 3.2×10⁻⁹, and OR=1.30 [1.19-1.42]and 1.31 [1.20-1.43], respectively).

To examine whether significant associations of these 54 SNPs wereindependent of each other, logistic regression models were evaluated foreach possible pair of SNPs. Attempting to identify the most parsimoniousset of SNPs that showed independent association with DVT risk, it wasobserved that the two strongest markers in F11, rs3756011 and rs2289252,remained significant after adjustment for any other markers except eachother. Furthermore, they were the only markers whose significance wasnot appreciably attenuated after adjustment by other markers. Because LDbetween rs3756011 and rs2289252 was very high (r²=0.98), furtheranalysis only included rs2289252.

To determine if any of the other markers made contributions to DVT risk,a search was carried out for those markers that were significantlyassociated with DVT after adjustment for rs2289252, which lead to theidentification of 17 markers. Significance of these 17 markers wasmodest after the adjustment (P ranged from 0.0043 to 0.046). Withinthese markers, six were identified that were in high LD with one of theother significant markers (r²>0.95); the marker with the weakerassociation was removed from the list of 17 markers, leaving 11 markers.

To further examine the relationship between the above 11 markers andrs2289252, the markers were then tested in another large DVTcase-control study (MEGA-2: 1,314 cases and 2,877 controls). Furtherstatistical analyses was performed in the three sample sets combinedinstead of using a discovery-replication approach, as the formerprovides greater power (Skol et al., Nat Genet 38, 209-3 (2006)). Alleleven SNPs remained significant in a combined analysis of all samples(Mantel-Haenszel P<0.05, Table 18).

To identify a subset of the 11 SNPs that independently contributed tothe association signals, two different analyses were performed: forwardstepwise logistic regression and multiple logistic regressions. Forforward stepwise logistic regression analysis, the selection procedurerequired a P-value<0.05 as a criterion for entry into the model wheresample set, sex and age were covariates. A final model was derived thatcontained 3 markers, rs2289252, rs2036914 and rs13146272 (Table 14). Noother SNPs were able to enter the model at a significance threshold of0.05. The multiple logistic regression analysis identified rs2289252 asthe most significant association after adjustment for age, sex and study(OR [95% CI]=1.21 [1.11-1.32]). The next strongest associations werers2036914 (OR [95% CI]=1.13 [0.98-1.32) and rs13146272 (OR [95% CI]=1.09[0.98 to 1.21]). Thus these three markers were the most informative onesamong those interrogated in this study.

Two of the independent markers, rs2289252 (the same marker as reportedin Smith et al., JAMA 297, 489-98 (2007)) and rs2036914, are in F11, andthe third one, rs13146272, is in CYP4V2. All three markers appeared tooperate in an additive model, with odds ratios up to 1.84 for the riskhomozygote (Table 15). LD was modest between the two F11 markers(r²=0.38) and low between either of the F11 markers and the CYP4V2marker (r²=0.12 and 0.04, respectively) (Table 19). These markers arecommon (for example, ˜27% of the population tested in these sample setsare risk homozygote carriers of rs2036914), indicating high DVT riskamong a sizable fraction of the population. Furthermore, in contrast tothe infrequent Factor V Leiden variant and prothrombin G20210Apolymorphism that are mostly present in Caucasians, all threeindependent SNPs noted here are of similarly high frequencies in Asiansand Africans, indicating that they also make a substantial contributionto DVT risk in these populations.

Both the F11 SNPs, rs2036914 and rs2289252, are intronic, thus thesemarkers (or variants in high LD) may alter transcriptional regulatoryelements such as an enhancer and these variants may modulate expressionof F11. Therefore, association of the individual genotype and the levelof FXI was tested in the LETS sample set. The genotype of rs2289252 wassignificantly associated with FXI levels (P_(trend)=2.1×10⁻²⁰, N=895).The genotype of rs2036914 has been shown to be associated with the levelof FXI (Bezemer et al., JAMA 299, 1306-14 (2008)). The third SNP,rs13146272, is a missense variant (K259Q) of CYP4V2. CYP4V2 may play arole in fatty acid and steroid metabolism, and mutations in the genecause autosomal recessive retinal dystrophy (Li et al., Am J Hum Genet74, 817-26 (2004)). However, given the correlation of the CYP4V2 markerwith the level of FXI (Bezemer et al., JAMA 299, 1306-14 (2008)), itsgenetic effect on DVT susceptibility may be indirectly mediated throughFXI protein. This indirect effect may arise from a long-rangetranscriptional regulatory element of F11 encompassing the CYP4V2 SNP orits proxies (for example, rs2292425, an intronic SNP also in CYP4V2,which is in perfect LD [r²=1]); rs13146272 lies 67 kb upstream of theF11 gene, and long range regulatory elements have been observed acrossmultiple genes (Kapranov et al., Nat Rev Genet. 8, 413-23 (2007)).Alternatively, the CYP4V2 SNP may be in high LD with another variant inor more proximal to the F11 gene that is capable of directly regulatingF11 expression.

For all three markers, risk allele carriers had higher levels of FXIthan those without the risk allele, and risk homozygote carriers hadhigher levels of FXI than the heterozygote carriers. In addition, therelative difference of the average FXI levels among individuals ofdifferent genotypes was greater for the F11 markers than for the CYP4V2marker. For example, the average level of FXI in risk homozygotecarriers was 119% for rs2289252, 119% for rs2036914, and 108% forrs13146272 relative to the non-carriers. Furthermore, in the model withall three SNPs, each risk allele of rs2289252 resulted in an increase of7.6 units of FXI levels on average (P=3.7×10⁻¹⁰; it had an effect of 8.8units and P=2.1×10⁻²⁰ prior to adjustment by the other two SNPs), whilethe effect of rs2036914 alleles was only 1.9 units of FXI level (P=0.15;compared to an effect of 7.2 and p=5.6×10⁻¹³ prior to adjustment), andthe effect of rs13146272 was 0.6 units per allele after adjustment(P=0.60; compared to an effect of 3.4 and P=0.002 prior to adjustment).The direction of the effect was consistent with the expected increase ofDVT risk with high levels of FXI (Meijers et al., N Engl J Med 342,696-701 (2000)).

To determine whether FXI levels contributed to the observed SNP-diseaseassociation, association of the three independent markers with DVT wasre-tested following adjustment by Factor XI levels. For each of thethree SNPs in the combined LETS and MEGA-1 sample sets, the adjustmentfor FXI levels lowered the risk estimates and increased the P values,but the association with DVT remained significant (Table 16).

In summary, the majority of the common genetic variants in theCYP4V2/KLKB1/F11 locus were analyzed. In addition, the large casecontrol collections, with a total of >8,000 individuals, offered highpower to not only convincingly implicate common SNPs of even modesteffect in disease susceptibility but also reasonably distinguish theirrelationship (dependence) among various markers. Three independent SNPs,in particular, in the CYP4V2/KLKB1/F11 locus were identified that areassociated with DVT. In addition, there was a strong correlation betweengenotype of each of these three independent markers and FXI levels.Directionality of the genotypic effect on DVT risk and that on FXIlevels were congruent with earlier evidence that individuals with highlevels of FXI are at elevated risk of DVT (Bezemer et al., JAMA 299,1306-14 (2008) and Meijers et al., N Engl J Med 342, 696-701 (2000)),and SNPs associated with higher increase in FXI show strongerassociation with disease risk. Furthermore, adjustment of SNP-diseaseassociation by FXI protein did not abate the observed association. Thesegenetic variants may directly or indirectly modulate F11 expression,thereby contributing to the differential risk of DVT, althoughprekallikrein and FXI expression may be co-regulated.

These markers may also be associated with other conditions such asmyocardial infarction (Doggen et al., Blood 108, 4045-51 (2006) andMerlo et al., Atherosclerosis 161, 261-7 (2002)) and ischemic stroke(Yang et al., Am J Clin Pathol 126, 411-5 (2006)), where high levels ofFXI may be a risk factor as well. Thus, in addition to their utility inpredicting DVT risk, these markers may also be useful for predicting anindividual's risk for myocardial infarction, ischemic stroke, and otherdiseases in which high levels of FXI are a risk factor for the disease.

Methods

LETS and MEGA Samples

The three case control sample sets used in this study included Caucasianindividuals, primarily Northwestern Europeans; all provided informedconsent. The Leiden Thrombophilia Study (LETS) sample set consisted of443 cases (43% male) with a first confirmed DVT and 453 controls (42%male) with no history of DVT or PE. The participants were 18 to 70 yearsold without cancer when enrolled in the study, with a mean age (±SD) of45 (±14) years for cases and 45 (±15) years for controls. The MultipleEnvironmental and Genetic Assessment (MEGA) study comprised participantsaged 18 to 80 years, cases with first DVT and controls without historyof DVT or PE. Two sample sets were derived from this study, MEGA-1 with1,398 cases (47% male) and 1,757 controls (48% male) and MEGA-2 with1,314 cases (48% male) and 2,877 controls (47% male). The mean ages ofthe cases and controls are 47±13 and 48±12 years in MEGA-1 and 48±13 and47±12 years in MEGA-2, respectively. The total sample size is 3,155cases and 5,087 controls. Additional information can be found in Bezemeret al., JAMA 299, 1306-14 (2008).

SNP Selection

Upon initial discovery of the association of CYP4V2 with DVT, additionalgenotyping and statistical analysis was carried out in a limited scope(Bezemer et al., JAMA 299, 1306-14 (2008)). In the study described herein Example Four, a comprehensive analysis of SNPs in the 4q35 locus andthose of putative functional significance was carried out. Thefine-mapping region was determined by examination of the LD structure atthe CYP4V2/KLKB1/F11 locus in the HapMap CEPH dataset and was defined bytwo SNP landmarks, rs4862644 at 187,294,806 bp and rs13150040 at187,494,774 bp on chromosome 4 (NCBI Build 36), encompassing 200 kbp.The targeted region covers the LD block containing the initialsignificant marker and a portion of the neighboring blocks and contains320 known SNPS (187 of these with allele frequency than 2%) in theHapMap dataset. Selected markers included those that capture the SNPdiversity in the defined region; they were identified by the taggerprogram, using the HapMap CEPH dataset and the following criteria:minimum allele frequency of 0.02 and pair wise r² threshold of 0.8.Additional markers included missense/nonsense SNPs and those that are inhigh LD with any of the three significant SNPs previously reported,rs13146272 in CYP4V2, rs2036914 and rs3756008, both in F11 (r²>0.2).

Genotyping

Genotyping of individual samples was determined by allele-specificreal-time PCR using primers designed and validated in Celera'shigh-throughput genotyping laboratory (Germer et al., Genome Res 10,258-66 (2000)). Case and control samples were randomly arrayed in384-well plates for the PCR reaction, and genotypes were assigned by anautomated algorithm and subjected to manual inspection of assayqualities by a technician without the knowledge of case and controlstatus. Genotyping accuracy in this laboratory has been consistentlyhigher than 99% (Li et al., Proc Natl Acad Sci USA 101, 15688-93(2004)).

Statistical Analyses

Hardy-Weinberg equilibrium for each genotyped SNP was examined in casesand controls separately by an exact test. Linkage disequilibriummeasurements, D′ and r² were calculated from the unphased genotype datausing LDMax in the GOLD package (Abecasis et al., Bioinformatics 16,182-3 (2000)). Odds ratios in individual sample sets were calculatedusing the observed allele counts. Allelic association of the SNPs withdisease was determined by the χ² test in individual sample sets and byMantel-Haenszel methods to combine odds ratios (OR) across the samplesets. P-values were 2 sided. Evidence for heterogeneity of effectsacross sample sets was examined by the Breslow-Day test (Breslow et al.,IARC Sci Publ, 5-338 (1980)). Logistic regression was used to estimateodds ratios while adjusting for covariates such as age, sex, sample set,and Factor XI levels. To assess the relative importance among thesignificant markers (reference Cordell and Clayton here), logisticregression models were performed for each possible pair of SNPs as wellas stepwise logistic regression models. These models assumed an additiveeffect of each additional risk allele on the log odds of DVT. Linearregression models were performed to estimate the effect of SNPs onFactor XI levels and to test for an increasing trend of mean Factor XIlevels assuming an additive effect of each additional risk allele for agiven SNP.

TABLE 14 SNPs in the final model by forward selection procedures inLETS, MEGA-1 and MEGA-2 samples combined SNP Model* OR (95% CI)** P***rs2289252 TT vs CC 1.49 (1.25-1.76) 3.8 × 10⁻⁶ CT vs CC 1.28 (1.13-1.45)1.0 × 10⁻⁴ rs2036914 CC vs TT 1.33 (1.11-1.59) 1.8 × 10⁻³ CT vs TT 1.19(1.03-1.38) 1.9 × 10⁻² rs13146272 AA vs CC 1.24 (1.05-1.46) 1.1 × 10⁻²AC vs CC 1.14 (0.97-1.34) 9.5 × 10⁻² *risk genotype vs referencegenotype **adjusted by age, sex, sample set, and other SNPs in the model***chi-square test

TABLE 15 Association of the three independently significant SNPs withDVT in LETS, MEGA-1 and MEGA-2 samples combined SNP/ Case Case ControlControl Gene Genotype (N) (%) (N) (%) OR (95% CI) P* rs2289252 TT 71623.5 849 17.1 1.84 (1.62-2.10) 1.7 × 10⁻²⁰ F11 TC 1511 49.6 2341 47.11.41 (1.27-1.57) CC 817 26.8 1785 35.9 1.00 (reference) rs2036914 CC1080 35.1 1364 27.4 1.84 (1.61-2.10) 6.5 × 10⁻¹⁹ F11 CT 1499 48.7 245049.3 1.42 (1.26-1.61) TT 499 16.2 1159 23.3 1.00 (reference) rs13146272AA 1391 47.2 1986 41.8 1.58 (1.29-1.76) 2.1 × 10⁻⁷ CYP4V2 AC 1263 42.82132 44.9 1.28 (1.09-1.49) CC 295 10.0 635 13.4 1.00 (reference)*logistic regression analysis adjusted by sample sets

TABLE 16 Association of rs2289252, rs13146272 and rs2036914 with DVT inthe LETS and MEGA-1 sample sets after adjustment by Factor XI SNP Model*OR (95% CI) P rs2289252 CT vs CC 1.27 (1.09-1.47) 0.002 TT vs CC 1.39(1.15-1.69) 0.001 rs2036914 CT vs TT 1.26 (1.07-1.48) 0.006 CC vs TT1.42 (1.19-1.70) <0.001 rs13146272 CA vs CC 1.27 (1.04-1.56) 0.018 AA vsCC 1.40 (1.14-1.71) 0.001 *adjusted for FXI and study

TABLE 17 Significant markers (P < 0.05) in the LETS and MEGA-1 samplesets combined Risk Allele Allele Frequency SNP Location (bp)* SNP TypeGene Symbol Risk Reference Case Control OR (95% CI) P rs1877321187,316,011 intron FAM149A G A 0.784 0.763 1.13 (1.02-1.26) 2.24E−02rs10017419 187,345,132 intergenic T G 0.442 0.415 1.12 (1.02-1.22)1.62E−02 rs10866290 187,351,473 intron CYP4V2 C T 0.357 0.335 1.1(1-1.21) 4.62E−02 rs10013653 187,352,626 intron CYP4V2 A C 0.473 0.4331.18 (1.08-1.28) 3.47E−04 rs7682918 187,352,835 intron CYP4V2 T C 0.4360.401 1.15 (1.05-1.26) 1.82E−03 rs7684025 187,353,221 intron CYP4V2 A G0.508 0.464 1.19 (1.09-1.3) 9.32E−05 rs4862662 187,355,656 intron CYP4V2T G 0.458 0.416 1.19 (1.09-1.3) 1.67E−04 rs13146272 187,357,205 missenseCYP4V2 A C 0.682 0.642 1.2 (1.09-1.31) 1.51E−04 rs3817184 187,359,298intron CYP4V2 T C 0.464 0.421 1.19 (1.09-1.3) 1.06E−04 rs2276917187,366,989 intron CYP4V2 A G 0.639 0.615 1.11 (1.01-1.21) 2.75E−02rs1877320 187,368,273 intron CYP4V2 A G 0.905 0.885 1.24 (1.08-1.44)3.12E−03 rs9995366 187,368,378 intron CYP4V2 C T 0.902 0.882 1.22(1.06-1.41) 5.98E−03 rs2102575 187,368,498 intron CYP4V2 A G 0.910 0.8891.26 (1.09-1.46) 2.25E−03 rs1053094 187,370,025 3UTR CYP4V2 T A 0.5450.497 1.21 (1.11-1.32) 2.36E−05 rs6842047 187,370,570 3UTR CYP4V2 C A0.910 0.891 1.23 (1.06-1.43) 6.50E−03 rs4253236 187,385,065 5′ near geneKLKB1 C T 0.677 0.637 1.19 (1.09-1.31) 1.93E−04 rs2048 187,385,127 5′near gene KLKB1 T G 0.565 0.515 1.23 (1.12-1.34) 7.13E−06 rs4253238187,385,381 5′ near gene KLKB1 T C 0.564 0.515 1.22 (1.1-1.34) 8.52E−05rs1912826 187,386,534 intron KLKB1 A G 0.565 0.515 1.22 (1.12-1.34)9.43E−06 rs4253252 187,394,452 intron KLKB1 G T 0.566 0.516 1.22(1.12-1.33) 1.04E−05 rs3733402 187,395,028 missense KLKB1 A G 0.5660.518 1.22 (1.11-1.33) 1.30E−05 rs4253260 187,399,071 intron KLKB1 G C0.859 0.835 1.2 (1.07-1.36) 2.86E−03 rs4253302 187,410,482 intron KLKB1A G 0.859 0.836 1.19 (1.06-1.35) 4.57E−03 rs4253303 187,410,540 intronKLKB1 A G 0.442 0.398 1.2 (1.1-1.31) 6.06E−05 rs4253311 187,411,677intron KLKB1 G A 0.565 0.519 1.21 (1.1-1.32) 3.37E−05 rs2292423187,412,716 intron KLKB1 A T 0.465 0.417 1.22 (1.11-1.33) 1.38E−05rs925453 187,416,204 synonymous KLKB1 C T 0.708 0.687 1.11 (1.01-1.22)3.52E−02 rs3087505 187,416,480 3UTR KLKB1 G A 0.910 0.889 1.26(1.09-1.46) 2.01E−03 rs4253332 187,416,797 3′ near gene C T 0.701 0.6791.11 (1-1.22) 3.93E−02 rs6844764 187,418,527 intergenic G C 0.587 0.5611.11 (1.02-1.22) 1.90E−02 rs3756008 187,422,379 5′ near gene T A 0.4680.408 1.27 (1.17-1.39) 7.66E−08 rs925451 187,424,563 intron F11 A G0.458 0.392 1.31 (1.19-1.43) 4.44E−09 rs4253399 187,425,088 intron F11 GT 0.450 0.388 1.29 (1.18-1.41) 2.18E−08 rs3822057 187,425,146 intron F11C A 0.551 0.494 1.26 (1.15-1.37) 3.64E−07 rs4253405 187,427,804 intronF11 A G 0.664 0.628 1.17 (1.07-1.28) 7.14E−04 rs2036914 187,429,475intron F11 C T 0.591 0.526 1.3 (1.19-1.42) 4.89E−09 rs1593 187,432,545intron F11 A T 0.896 0.873 1.26 (1.1-1.45) 1.09E−03 rs4253418187,436,491 intron F11 G A 0.966 0.953 1.39 (1.1-1.74) 4.56E−03rs2241817 187,437,995 intron F11 A G 0.674 0.645 1.14 (1.04-1.25)5.03E−03 rs4253422 187,441,996 intron F11 C G 0.850 0.834 1.13 (1-1.28)4.31E−02 rs3822058 187,443,174 intron F11 G A 0.675 0.644 1.15(1.05-1.26) 3.15E−03 rs3756011 187,443,243 intron F11 A C 0.485 0.4201.3 (1.19-1.42) 5.15E−09 rs2289252 187,444,375 intron F11 T C 0.4850.419 1.31 (1.2-1.43) 3.23E−09 rs4253430 187,447,058 3UTR F11 G C 0.6760.645 1.15 (1.05-1.26) 3.61E−03 rs11938564 187,449,128 intergenic T G0.807 0.786 1.14 (1.02-1.27) 1.85E−02 rs13136269 187,454,002 intergenicT C 0.758 0.721 1.21 (1.1-1.34) 1.49E−04 rs13116273 187,454,880intergenic G A 0.758 0.723 1.2 (1.08-1.32) 4.05E−04 rs10025152187,462,298 intergenic G A 0.857 0.829 1.23 (1.09-1.39) 8.43E−04rs1008728 187,463,667 intergenic T C 0.656 0.622 1.16 (1.06-1.27)1.91E−03 rs12500826 187,464,445 intergenic C T 0.658 0.624 1.16(1.06-1.27) 1.91E−03 rs13133050 187,467,731 intergenic C A 0.696 0.6721.11 (1.01-1.23) 2.58E−02 rs6552971 187,475,382 intergenic A G 0.5290.505 1.1 (1.01-1.2) 3.44E−02 rs6552972 187,475,398 intergenic C T 0.2240.197 1.17 (1.05-1.31) 3.72E−03 rs9993749 187,476,843 intergenic T G0.275 0.254 1.11 (1.01-1.23) 3.79E−02 *on chromsome 4, based on NCBIBuild 36

For the SNPs provided in Table 17, SEQ ID NOs of exemplary sequences areindicated in Tables 1-2, with the exception of the following SNPs forwhich SEQ ID NOs of exemplary genomic context sequences provided in theSequence Listing are as follows:

rs10017419=SEQ ID NO:2559

rs10866290=SEQ ID NO:2560

rs2276917=SEQ ID NO:2561

rs1877320=SEQ ID NO:2562

rs9995366=SEQ ID NO:2563

rs2102575=SEQ ID NO:2564

rs6842047=SEQ ID NO:2565

rs2048=SEQ ID NO:2566

rs4253238=SEQ ID NO:2567

rs1912826=SEQ ID NO:2568

rs4253252=SEQ ID NO:2569

rs4253260=SEQ ID NO:2570

rs4253311=SEQ ID NO:2571

rs925453=SEQ ID NO:2572

rs4253332=SEQ ID NO:2573

rs1593=SEQ ID NO:2574

rs4253422=SEQ ID NO:2575

rs11938564=SEQ ID NO:2576

rs10025152=SEQ ID NO:2577

rs1008728=SEQ ID NO:2578

rs13133050=SEQ ID NO:2579

rs9993749=SEQ ID NO:2580

TABLE 18 Significant markers (P < 0.05) in the LETS, MEGA-1 and MEGA-2sample sets combined Risk Allele Allele Frequency SNP Gene Symbol RiskReference Case Control OR P rs13146272 CYP4V2 C A 0.686 0.642 1.21(1.13-1.30) 2.88E−08 rs3817184 CYP4V2 C T 0.469 0.417 1.23 (1.16-1.32)1.63E−10 rs1053094 CYP4V2 A T 0.550 0.493 1.25 (1.17-1.33) 5.47E−12rs4253236 CYP4V2 T C 0.676 0.639 1.17 (1.09-1.25) 3.02E−06 rs3733402KLKB1 G A 0.568 0.517 1.23 (1.15-1.31) 3.35E−10 rs4253302 KLKB1 G A0.859 0.837 1.18 (1.08-1.30) 1.92E−04 rs4253303 KLKB1 G A 0.448 0.3951.24 (1.17-1.33) 4.44E−11 rs2292423 KLKB1 T A 0.468 0.411 1.25(1.18-1.34) 5.59E−12 rs2036914 F11 T C 0.594 0.521 1.34 (1.26-1.43)3.58E−19 rs4253418 F11 A G 0.966 0.956 1.31 (1.10-1.55) 1.43E−03rs2289252 F11 C T 0.483 0.406 1.35 (1.27-1.45) 2.96E−20

TABLE 19 Marker LD in the LETS, MEGA-1 and MEGA-2 sample sets combined(controls): D′ shown in the upper right triangle, r² shown in the lowerleft triangle rs13146272 rs3817184 rs1053094 rs4253236 rs3733402rs4253302 rs4253303 rs2292423 rs2036914 rs4253418 rs2289252 rs131462720.993 0.58 0.618 0.546 0.955 0.912 0.781 0.443 0.812 0.338 rs38171840.392 0.986 0.812 0.772 0.931 0.889 0.82 0.587 0.717 0.351 rs10530940.182 0.716 0.843 0.804 0.954 0.901 0.918 0.585 0.723 0.461 rs42532360.382 0.267 0.39 0.991 0.993 0.983 0.985 0.397 0.937 0.235 rs37334020.178 0.398 0.586 0.593 0.993 0.964 0.981 0.55 0.93 0.412 rs42533020.319 0.12 0.172 0.34 0.205 0.994 0.995 0.56 0.995 0.35 rs4253303 0.3020.72 0.544 0.356 0.565 0.125 0.979 0.659 0.932 0.37 rs2292423 0.2380.658 0.608 0.383 0.63 0.134 0.892 0.686 0.939 0.418 rs2036914 0.1180.227 0.307 0.097 0.298 0.066 0.26 0.303 0.968 0.773 rs4253418 0.0540.017 0.024 0.072 0.043 0.009 0.026 0.028 0.047 1 rs2289252 0.043 0.1170.149 0.021 0.108 0.016 0.131 0.17 0.376 0.031

Example Five SNPs Associated with Venous Thrombosis (Analysis in LETS,MEGA-1, and/or MEGA-2)

Tables 20-23 provide SNPs associated with VT, particularly DVT, in theLETS, MEGA-1, and/or MEGA-2 sample sets (these sample sets are describedin Examples One through Four above). Specifically, Table 20 providesunadjusted additive and genotypic association with DVT for 149 SNPs thatwere tested in both MEGA-1 and LETS, and were associated with DVT inboth of these sample sets (p-value cutoff <=0.05 in MEGA-1 and p-valuecutoff <=0.1 in LETS, in at least one model). Table 21 providesunadjusted association of 92 SNPs with DVT in LETS (p<=0.05) that havenot yet been tested in the MEGA-1 sample set, and Table 22 providesunadjusted association of 9 SNPs with DVT in MEGA-1 (p<=0.05) that havenot yet been tested in the LETS sample set. Table 23 provides age- andsex-adjusted association with DVT for 41 SNPs that were tested in thethree sample sets LETS, MEGA-1, and MEGA-2.

Example Six SNPs Associated with Recurrent Venous Thrombosis

Table 24 provides three SNPs that are examples of SNPs associated withrecurrence of VT (p-value cutoff <=0.05 in MEGA-1 and MEGA-2 combined).

The MEGA study has been described previously (Blom et al., JAMA 2005;293(6):715-722). An analysis for association of SNPs specifically withrecurrent VT in MEGA is ongoing. Briefly, approximately 4000 individuals(cases) who have had a first-time VT in MEGA are being followed-up forabout 5 years, and time to the next event (if any) is being recorded.Currently, this recurrent VT analysis in MEGA is approximately at thehalfway point, and approximately 600 recurrent cases have been recorded.Certain SNPs have been specifically identified as examples of SNPs thatare associated with recurrent VT, and these SNPs are provided in Table24 below. These SNPs are particularly useful for, for example,determining the risk for individual who has already had VT of havinganother occurrence of VT.

TABLE 24 Two examples of SNPs associated with VT recurrence in MEGA(combined) (p <= 0.05). VT No VT p-value Risk recurrence recurrence(Fisher Gene SNP allele Genotype (counts) (counts) OR 95% CI Exact) F5rs6025 A GG 406 2235 1 GA 101 387 1.44 1.13-1.83 0.004032 AA 5 16 1.720.63-1.72 0.355669 ABO rs8176719 O 121 793 1 non-O 447 2245 1.311.05-1.62 0.015636

Example Seven SNPs Associated with Pulmonary Embolism (PE)

Table 25 provides 52 SNPs that are examples of SNPs associated withpulmonary embolism (PE) (p-value cutoff <=0.05 in MEGA-1 and MEGA-2combined). SNPs associated with PE are also described in Example Threeabove. Example Three also provides further information regarding PE aswell as information pertaining to methods and study populations in MEGAfor determining associations with PE. Cases were individuals with aconfirmed PE and no history of VT, and controls were individuals with nohistory of either PE or VT. The SNPs provided in Table 25 had a p-value<=0.05 when comparing these cases and controls in the combined MEGA-1and MEGA-2 studies. These SNPs are particularly useful for, for example,determining an individual's risk for PE.

Example Eight SNPs Associated with Venous Thrombosis in Individuals Whohave Cancer

Table 26 provides 31 SNPs that are examples of SNPs that are associatedwith VT, particularly DVT, in individuals who have cancer (p-valuecutoff <=0.05 in MEGA-1 and MEGA-2 combined). The SNPs provided in Table26 had a p-value <=0.05 when comparing individuals (cases) in thecombined MEGA-1 and MEGA-2 studies who had both cancer (of any type) andDVT compared with individuals (controls) who had neither cancer nor DVT.These SNPs are particularly useful for, for example, determining riskfor VT in individuals who have cancer.

Example Nine Fine-Mapping/Linkage Disequilibrium SNPs Associated withVenous Thrombosis

Table 27 provides 123 SNPs associated with VT, particularly DVT, in LETS(p-value cutoff <=0.1 in LETS) based on fine-mapping/linkagedisequilibrium analysis. Table 27 provides additive association with DVTfor each SNP, as well as linkage disequilibrium data from Hapmap. Table27 specifically provides SNPs based on fine-mapping/linkagedisequilibrium analysis around the following target genes and SNPs (asindicated in Table 27): gene AKT3 (SNP hCV233148), gene SERPINC1 (SNPhCV16180170), gene RGS7 (SNP hCV916107), gene NR1I2 (SNP hCV263841),gene FGG (SNP hCV11503469), gene CYP4V2 (SNP hCV25990131), gene GP6 (SNPhCV8717873), and gene F9 (SNP hCV596331).

The AKT3 gene and SNP rs1417121/hCV233148 are an example of a targetaround which fine-mapping/linkage disequilibrium analysis was carriedout. Results of the association of AKT3 SNPs with DVT are provided inTable 27 (in LETS), as well as in Tables 28-29 below (which provideresults in MEGA-1 as well as in LETS (Table 29), and in MEGA-2 forrs1417121 (Table 28)).

SNP rs1417121/hCV233148 in the AKT3 gene was identified among 24,965SNPs tested in a functional genome scan (scan WGS38-V0013; Bezemer etal., JAMA 299, 1306-14 (2008)) and found by genotyping to be associatedwith DVT and PE in LETS, MEGA-1, and MEGA-2 with a p-value<0.05 and aconsistent risk allele in all three studies (Tables 28-29). The FDR forthis SNP is 0.044 in MEGA-2. To determine whether other SNPs in thisregion are associated with DVT, results from the HapMap Project wereused to identify a region surrounding SNP rs1417121/hCV233148(chr1:241735973). This region contained 228 SNPs with allelefrequencies>2% (HapMap NCBI build 36, 2005). Allele frequencies andlinkage disequilibrium were calculated from the SNP genotypes in theHapMap CEPH population, which includes Utah residents with ancestry fromnorthern and western Europe. 36 of these 228 SNPs were selected forgenotyping in LETS as surrogates for 205 of these 228 SNPs. Thus, these205 SNPs included the 36 SNPs that were directly genotyped plus 169 SNPsthat were in strong linkage disequilibrium (r²>0.8) with at least one ofthe 36 genotyped SNPs (these 36 SNPs may be referred to as “taggingSNPs”). The 36 tagging SNPs were chosen using pairwise tagging in Tagger(de Bakker et al. 2005) (implemented in Haploview (Barrett et al.2005)). 62 SNPs (including the 36 tagging SNPs) were initiallyinvestigated in LETS, and 29 SNPs that were equally or more stronglyassociated with DVT in LETS than SNP rs1417121/hCV233148 wereinvestigated in MEGA-1. 20 SNPs were associated with DVT in both LETSand MEGA-1 with an additive p-value<0.05 and a consistent risk allele(these 20 SNPs are shown in Table 29 below).

TABLE 28 Age and sex-adjusted associations of an AKT3 SNP with DVT inMEGA-2 Gene Symbol Case Control (RS Number) Chr:B36 Region parameter(frequency) (frequency) P value Odds ratio (95% CI) FDR* AKT3(rs1417121) 1:241735973 CC_vs_GG 126 (0.1)  214 (0.08) 0.009 1.38(1.08-1.75) CG_vs_GG 494 (0.4) 1074 (0.39) 0.333 1.07 (0.93-1.24) G G626 (0.5) 1458 (0.53) ref ref 0.044 C_vs_G    (0.27) 0.018 1.13(1.02-1.26)

TABLE 29 Additive associations of 20 replicated AKT3 fine-mapping SNPsin LETS and MEGA-1 LETS MEGA-1 additive p- p- annotation comparisonvalue OR (95% CI) value OR (95% CI) AKT3 (rs10737888) C_vs_A 4E−05 1.58(1.27-1.96) 0.001 1.21 (1.08-1.36) AKT3 (rs6656918) G_vs_A 5E−05 1.56(1.26-1.94) 0.003 1.19 (1.06-1.34) AKT3 (rs1538773) G_vs_T 1E−04 1.55(1.24-1.92) 0.006 1.18 (1.05-1.32) AKT3 (rs10927041) C_vs_T 0.0001 1.59(1.26-2) 0.007 1.18 (1.05-1.34) AKT3 (rs2290754) C_vs_A 0.0001 1.57(1.24-1.97) 0.019 1.15 (1.02-1.3) AKT3 (rs7517340) T_vs_C 0.0002 1.58(1.24-2) 0.003  1.2 (1.07-1.36) AKT3 (rs10754807) A_vs_G 0.0002 1.57(1.24-1.98) 0.002 1.21 (1.07-1.36) AKT3 (rs320339) T_vs_G 0.0003 1.51(1.21-1.9) 0.002 1.21 (1.07-1.37) AKT3 (rs1417121) C_vs_G 0.0003 1.45(1.18-1.78) 0.001  1.2 (1.08-1.33) AKT3 (rs6671475) G_vs_A 0.0004 1.52(1.21-1.91) 0.014 1.16 (1.03-1.31) AKT3 (rs1058304) T_vs_C 0.0004 1.45(1.18-1.78) 0.008 1.16 (1.04-1.29) AKT3 (rs1458023) C_vs_T 0.0004  1.5(1.2-1.88) 0.006 1.18 (1.05-1.33) AKT3 (rs12048930) T_vs_C 0.001 1.47(1.17-1.86) 0.026 1.15 (1.02-1.29) AKT3 (rs1578275) C_vs_G 0.0012 1.49(1.17-1.89) 0.047 1.14 (1-1.29) AKT3 (rs10927035) C_vs_T 0.0019 1.36(1.12-1.66) 0.002 1.18 (1.06-1.3) AKT3 (rs12140414) C_vs_T 0.0026 1.44(1.14-1.82) 0.04 1.14 (1.01-1.3) AKT3 (rs12037013) A_vs_G 0.0029 1.49(1.15-1.93) 0.021 1.18 (1.02-1.35) AKT3 (rs12744297) G_vs_A 0.0058 1.32(1.08-1.61) 0.001 1.19 (1.07-1.32) AKT3 (rs10927065) A_vs_C 0.01  1.4(1.08-1.8) 0.013 1.18 (1.04-1.34) AKT3 (rs12045585) A_vs_G 0.0354 1.32(1.02-1.72) 0.002 1.25 (1.08-1.43)

Example Ten Additional SNPs in Linkage Disequilibrium with VenousThrombosis-Associated Interrogated SNPs

An additional analysis was conducted to identify additional SNP markersin linkage disequilibrium (LD) with SNPs which have been found to beassociated with VT, such as shown in the tables and described in theExamples. Briefly, the power threshold (T) was set at 51% for detectingdisease association using LD markers. This power threshold is based onequation (31) above, which incorporates allele frequency data fromprevious disease association studies, the predicted error rate for notdetecting truly disease-associated markers, and a significance level of0.05. Using this power calculation and the sample size, a thresholdlevel of LD, or r² value, was derived for each interrogated SNP (r_(T)², equations (32) and (33)). The threshold value r_(T) ² is the minimumvalue of linkage disequilibrium between the interrogated SNP and its LDSNPs possible such that the non-interrogated SNP still retains a powergreater or equal to T for detecting disease-association.

Based on the above methodology, LD SNPs were found for the interrogatedSNPs. LD SNPs are listed in Table 4, each associated with its respectiveinterrogated SNP. Also shown are the public SNP IDs (rs numbers) forinterrogated and LD SNPs, the threshold r² value and the power used todetermine this, and the r² value of linkage disequilibrium between theinterrogated SNP and its matching LD SNP. As an example, in Table 4,VT-associated interrogated SNP hCV11503414 (rs2066865) was calculated tobe in LD with hCV11503416 (rs2066864) at an r_(T) ² value of 1, using51% power, thus establishing SNP hCV11503416 as a marker associated withVT as well.

In general, the threshold r_(T) ² value can be set such that one ofordinary skill in the art would consider that any two SNPs having an r²value greater than or equal to the threshold r_(T) ² value would be insufficient LD with each other such that either SNP is useful for thesame utilities, such as determining an individual's risk for VT. Forexample, in various embodiments, the threshold r_(T) ² value used toclassify SNPs as being in sufficient LD with an interrogated SNP (suchthat these LD SNPs can be used for the same utilities as theinterrogated SNP, for example, such as determining VT risk) can be setat, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98,0.99, 1, etc. (or any other r² value in-between these values). Thresholdr_(T) ² values may be utilized with or without considering power orother calculations.

All publications and patents cited in this specification are hereinincorporated by reference in their entirety. Modifications andvariations of the described compositions, methods and systems of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments andcertain working examples, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the above-described modes for carryingout the invention that are obvious to those skilled in the field ofmolecular biology, genetics and related fields are intended to be withinthe scope of the following claims.

TABLE 3 Marker Alleles Primer 1 (Allele-specific Primer) hCV10008773 T/CCACGTGTGCTCACTTACAGAT (SEQ ID NO: 1588) hCV11342584 A/TGGCTGCTAGCCAAATACTATTA (SEQ ID NO: 1591) hCV11466393 C/GGGATGGAATGTTTTCCCTAAC (SEQ ID NO: 1594) hCV11503414 A/GTGTTTCCTAAGACTAGATACATGGTAT (SEQ ID NO: 1597) hCV11503431 C/TCCAGTGCTTGCCTTCTC (SEQ ID NO: 1600) hCV11503469 A/TAGTTTACAATCTAATGCAGTGGT (SEQ ID NO: 1603) hCV11503470 C/TAAAATGATGGGAAGTTAGGG (SEQ ID NO: 1606) hCV11541681 C/GCCACCTTCTCTTCAGATTCAC (SEQ ID NO: 1609) hCV11559107 A/GTGAGATTTTGAAGACATCTGGTA (SEQ ID NO: 1612) hCV11629656 G/TCCCCAATAAAAGGACACAGTTAG (SEQ ID NO: 1615) hCV11629657 A/GTGTCCTAAGATTAGCTAATATTTAACAT (SEQ ID NO: 1618) hCV11633415 C/TCCCAGAGGTCTACTATCTGAC (SEQ ID NO: 1621) hCV11726971 A/GGCAAGGTGTCTCCGAATTAT (SEQ ID NO: 1624) hCV11786147 G/TCGTGCGTGAATTGAATGG (SEQ ID NO: 1627) hCV11786258 A/GGTGGAGAATACCCACTCAGT (SEQ ID NO: 1630) hCV11853483 A/GCACACACATCTTTAAAATCCATTCTATT (SEQ ID NO: 1633) hCV11853496 A/TCCTTTCTCACCTGATAGAATGAGT (SEQ ID NO: 1636) hCV11922386 C/TCCTGGCCCTTTCCTACG (SEQ ID NO: 1639) hCV11942562 A/G ACGAATGTGATGGCCACA(SEQ ID NO: 1642) hCV11962159 C/T ATTAAGCAACTGGTTTCCG (SEQ ID NO: 1645)hCV11975250 T/C AGGACAAAATACCTGTATTCCTT (SEQ ID NO: 1648) hCV11975296T/C CAGTCCATGGTTCCTTCAT (SEQ ID NO: 1651) hCV11975651 C/GCACCTTCCCCACTCTCTTAG (SEQ ID NO: 1654) hCV11975658 A/GGGTGACAGGGGAGAAAAGA (SEQ ID NO: 1657) hCV1198623 C/GCCATGCCTGATACAGAAGAC (SEQ ID NO: 1660) hCV1202883 G/A GCGTGATGATGAAATCGG(SEQ ID NO: 1663) hCV12066124 C/T GCAGCTTTTGCCAGTAAAGAC (SEQ ID NO:1666) hCV12073840 C/T ACGGACACTGGACATACC (SEQ ID NO: 1669) hCV12086148A/G GTGAAGGTTTCCCTTTAAGTTACT (SEQ ID NO: 1672) hCV12092542 T/CGCCTTGTCTTCAATTTTGGT (SEQ ID NO: 1675) hCV12098639 C/G GGATGTGGCTTCCCC(SEQ ID NO: 1678) hCV134275 A/G GGTGCTTAGAATACATCAACAAAAT (SEQ ID NO:1681) hCV134278 C/T TAACCTGATCCATTATCCAAGATAC (SEQ ID NO: 1684)hCV1376206 C/T AGCAGGCTACTACTCCTTC (SEQ ID NO: 1687) hCV1376207 C/GCGTACAGACAGCCGAGG (SEQ ID NO: 1690) hCV1376227 A/CTCTCAACTTGGCTATCTTACAAATA (SEQ ID NO: 1693) hCV1376246 A/CCTTATTGAGTTCATCATTAAAGTCATCT (SEQ ID NO: 1696) hCV1376342 C/TACTCACCAGTTGTGAAGACTTC (SEQ ID NO: 1699) hCV1420741 C/GCAGGCTTTAAGGACAGGC (SEQ ID NO: 1702) hCV1455329 A/GCATGTTTTGTGAACAAAGATTCCAT (SEQ ID NO: 1705) hCV1547677 A/GAGGTGACAGTCCCAACACT (SEQ ID NO: 1708) hCV15755949 A/GAATACTTAGTTCTCCCCTCCATAA (SEQ ID NO: 1711) hCV15793897 A/GAGCTCTGAGTGCACTGTGTT (SEQ ID NO: 1714) hCV15860433 C/TACCCAAGACTTAGTAAACATTCAG (SEQ ID NO: 1717) hCV15864094 A/GGTGGATCAAGCTTCGTTGTTAT (SEQ ID NO: 1720) hCV15871021 G/AAAATCTTGCTCTTTATGAGTATTTG (SEQ ID NO: 1723) hCV15885425 A/CCATTTACAATGTAACAGCAAAACCA (SEQ ID NO: 1726) hCV15947925 C/TGCTCCAGGACAGAGAACG (SEQ ID NO: 1729) hCV15949414 A/GGGCTTTCATAATGCAAATGT (SEQ ID NO: 1732) hCV15952952 A/GAAAGTGGAGAAGGCTCTGAT (SEQ ID NO: 1735) hCV15953063 A/GGTTGGAAATAATGTAGGATGAAGACA (SEQ ID NO: 1738) hCV15956034 A/CCACTGAGCTGAAATGATCCATA (SEQ ID NO: 1741) hCV15956054 C/TCACCCAGTGCAGATTCAC (SEQ ID NO: 1744) hCV15956055 G/T GCAAGAAGGCAAGTCCC(SEQ ID NO: 1747) hCV15956059 C/T TGTAGTTGAAGGACAGAGTGG (SEQ ID NO:1750) hCV15956077 A/G TTACTCTAACACAGGGTTCCA (SEQ ID NO: 1753)hCV15968043 A/T GCCCAGTTTCAAACAGGA (SEQ ID NO: 1756) hCV15977624 A/GGTCCTCTTCACCAAGGAGT (SEQ ID NO: 1759) hCV15990789 A/G TGAACCTGAGCGTGTCAA(SEQ ID NO: 1762) hCV16000557 C/T ACAAAGTCACACCGAATCG (SEQ ID NO: 1765)hCV1605386 A/G AGTGGGAAACACACAGAAATTTA (SEQ ID NO: 1768) hCV16135173 C/GGGCAACCTCAACACAGAC (SEQ ID NO: 1771) hCV16170613 A/G ACAGCAGGCATTGTTTTCT(SEQ ID NO: 1774) hCV16172935 A/G GGAGTTACACCCATAAACCAT (SEQ ID NO:1777) hCV16177220 C/T ATCTGGTGGTCATTCAAATG (SEQ ID NO: 1780) hCV16180170C/T GGGAGAGCACTTGAAATGAC (SEQ ID NO: 1783) hCV1650632 C/TTCATCCAGCCACTCC (SEQ ID NO: 1786) hCV1678674 C/TGGCTTCAAAGTGATAAATTCTATATTCG (SEQ ID NO: 1789) hCV1678682 G/TGGACACAACTCATTATTCTGGG (SEQ ID NO: 1792) hCV1703855 C/TAACGAATGGCATGTATTTTATGG (SEQ ID NO: 1795) hCV1703867 C/TCGATGATTTTGTTCTCATGTTCG (SEQ ID NO: 1798) hCV1703892 A/TCCTGTTGCATTCTGGATACT (SEQ ID NO: 1801) hCV1703910 A/GACCTATGTAACACACCCTTCTATT (SEQ ID NO: 1804) hCV1723643 A/CACCCTCACAGCTCTGAAGA (SEQ ID NO: 1807) hCV1825046 C/T TGCACAGTCCCCTGAC(SEQ ID NO: 1810) hCV1833991 C/T GGGAGCCTTAATAAGATTAACAGC (SEQ ID NO:1813) hCV1834242 A/G CCTACTTTCACAAACATATCTTTGAA (SEQ ID NO: 1816)hCV1841975 A/T TCGTGGAGATACTGCAAGTT (SEQ ID NO: 1819) hCV1842260 G/TTCTCAGGCACCTGGATTAG (SEQ ID NO: 1822) hCV1859855 C/TGGCCTCACTAGAGAAGGAGAG (SEQ ID NO: 1825) hCV1874482 A/GAAAGGTTTCTTCTGATCACTGAT (SEQ ID NO: 1828) hCV18996 C/TTGAAGTAATACTGGAGATCAAATTAC (SEQ ID NO: 1831) hCV1900162 C/TCAGTATACCTAGAGCATAGTGG (SEQ ID NO: 1834) hCV1937195 A/GCACAGGGCACAGATAACT (SEQ ID NO: 1837) hCV1974936 C/T TGTGCACAAAGATAGGTCAC(SEQ ID NO: 1840) hCV1974951 A/G CGGGACACCATCCACA (SEQ ID NO: 1843)hCV1974967 A/G CACATCCAACGAGAAATTGCTA (SEQ ID NO: 1846) hCV2017876 A/GACTGCTTCCAGAAGATCAAGT (SEQ ID NO: 1849) hCV2086329 A/G CCCAGCCACACTGTTGA(SEQ ID NO: 1852) hCV2103346 C/T AGGAGCCATGATGCCC (SEQ ID NO: 1855)hCV2103392 C/T CCTCCTCCATGAAGCTGTC (SEQ ID NO: 1858) hCV2144411 A/GAAGCTCCGGGGTTATTGT (SEQ ID NO: 1861) hCV2211618 C/G GGCCATGTGCTGCCATC(SEQ ID NO: 1864) hCV22272267 A/G CTGGCAGCGAATGTTAT (SEQ ID NO: 1867)hCV2288095 C/T TGAGTTAATATTTGTGTAAAGTATGATGTTTAG (SEQ ID NO: 1870)hCV2303891 C/G CACAGTTCTCTGGCTTTTTG (SEQ ID NO: 1873) hCV233148 C/GTCATCACAGGACATTTATGAGAAG (SEQ ID NO: 1876) hCV2403368 C/GAAAGGTGAGCTCCACCATAC (SEQ ID NO: 1879) hCV2456747 A/GCCTCCACTAGAAGACACTACTACTTT (SEQ ID NO: 1882) hCV2494846 G/TCTTCTTCCCTTCGCTCTG (SEQ ID NO: 1885) hCV2532034 C/T CTGAAGCGCAACCATAAC(SEQ ID NO: 1888) hCV25473516 T/C CCACCCAATGCCAAGT (SEQ ID NO: 1891)hCV25474413 A/C GCATTCACAGTGTTCTCATTATAAT (SEQ ID NO: 1894) hCV25474414G/T CTGCAGAGCTGTAAGAGTG (SEQ ID NO: 1897) hCV25596789 C/GTCTGCTCCATTTTTCTCATG (SEQ ID NO: 1900) hCV25602230 G/T AGCTGAGGAGAGTCCG(SEQ ID NO: 1903) hCV25611352 C/T AATAATTGTAACTCTAGAACAAAAGTATTC (SEQ IDNO: 1906) hCV25615302 C/T GTTCCAGTTCCGATAGC (SEQ ID NO: 1909)hCV25620145 A/G CACACCAGCAATGATGAAACT (SEQ ID NO: 1912) hCV25634754 C/TGTCACTTATTTGAATCCCATTGC (SEQ ID NO: 1915) hCV25649928 G/AAAGACTTTTTCCAGGAATGC (SEQ ID NO: 1918) hCV25748719 T/C CGGCAGCCAATGACAT(SEQ ID NO: 1921) hCV2575036 A/G CAGTTTATGCCTGCAACAAT (SEQ ID NO: 1924)hCV25752810 C/A GCCCATAAGGAGACAGAAAAG (SEQ ID NO: 1927) hCV25767872 A/GCACCATGTGTGTGTTCCAT (SEQ ID NO: 1930) hCV25768636 A/GAGAATTTGGCCACAAAGAGT (SEQ ID NO: 1933) hCV2590858 C/TGAGTGAGAATTCTGTCAAGAGG (SEQ ID NO: 1936) hCV25932979 A/GAAAAGAGGGAGTAAACAACTGT (SEQ ID NO: 1939) hCV25951992 A/CCTGGAAAGATGGAGGCAT (SEQ ID NO: 1942) hCV25959466 T/C AAGCGATTCCTCAGCAGT(SEQ ID NO: 1945) hCV25959498 G/A ACAACATAAAACTGACTTGGAAG (SEQ ID NO:1948) hCV25990131 A/C TGTTGGTAAAAGTATGTAGGATCTT (SEQ ID NO: 1951)hCV25991132 A/G CCAGGAATGGAGACCATCT (SEQ ID NO: 1954) hCV25995678 C/TTCTGTCTTCCACAACCAAAG (SEQ ID NO: 1957) hCV25996277 A/TTATCTCCTTCAAAGGATGCA (SEQ ID NO: 1960) hCV26034142 C/TCAACCTAATTTAAGCCATCATTAACG (SEQ ID NO: 1963) hCV26034157 C/TCAACTCAAACAGGACACTGAG (SEQ ID NO: 1966) hCV26038139 A/GTCAGCTGGCGAAGTTGA (SEQ ID NO: 1969) hCV2605707 C/GGCTGTTAATTCAGGAGGTAAAGC (SEQ ID NO: 1972) hCV26175114 A/GCCAGTCATCTCTGCAGAAAAA (SEQ ID NO: 1975) hCV26265231 A/GGGGATAAATATTACAAACCCATGCTA (SEQ ID NO: 1978) hCV26338456 A/GCACAGAAGATACAGCAAATGGAA (SEQ ID NO: 1981) hCV26338482 C/TAAACAGTAACAGGCTCAGC (SEQ ID NO: 1984) hCV26338512 A/G CAGGCCTCGGAAAATGAA(SEQ ID NO: 1987) hCV26338513 C/T CGCACTTTTAGTGGCTGG (SEQ ID NO: 1990)hCV263841 A/C AGCTAATACTCCTGTCCTGAAA (SEQ ID NO: 1993) hCV26719108 C/TGCAGGGGCATTGGTG (SEQ ID NO: 1996) hCV26719113 C/TCTTACGATTAGTTCCAACATGAATAC (SEQ ID NO: 1999) hCV26719121 C/TCCCACTAAGCACAGGAAAG (SEQ ID NO: 2002) hCV26719154 C/T TGGTCTGTGCCCTCAG(SEQ ID NO: 2005) hCV26719227 A/C TGCCTTGGATATGCTTTAAAGAT (SEQ ID NO:2008) hCV26887403 A/C CTAGCACTGGAACGATAATAAAGA (SEQ ID NO: 2011)hCV26887434 A/C GACTTTACGACTAATTAGGTATAAAGGTTA (SEQ ID NO: 2014)hCV26887464 A/G GCAGGTCAGATAACTTCTTTATGA (SEQ ID NO: 2017) hCV26895255C/T CACCGTATTCAGCTGAGAC (SEQ ID NO: 2020) hCV2699725 C/GGTACCTCTTGGTCTCTCTCC (SEQ ID NO: 2023) hCV27020269 C/GCCAGTTTTGCACATTTAAAGATACG (SEQ ID NO: 2026) hCV2706410 C/TCCTCCATGTCATCCTACG (SEQ ID NO: 2029) hCV27102953 C/TTTAGTGTAATGGGCAAGACG (SEQ ID NO: 2032) hCV27102978 A/C CTCCTCCTGTCTCCGTT(SEQ ID NO: 2035) hCV27103080 G/T GGGATGTGCAACCCG (SEQ ID NO: 2038)hCV27103182 C/T GGCATCTCTCAATCCCTACG (SEQ ID NO: 2041) hCV27103188 A/GTGTTTGGACAATGACTTGGAAAT (SEQ ID NO: 2044) hCV27103189 A/GAAGAGGTCAAGCCAATGAAAT (SEQ ID NO: 2047) hCV27103207 A/G GGCTGCCAGGGACAT(SEQ ID NO: 2050) hCV2716314 A/C GGCATACAAATTCAAAATACTGTATA (SEQ ID NO:2053) hCV2734332 A/G GCCATGTTGACTCGAGAAT (SEQ ID NO: 2056) hCV2744023A/G CTACCTGTGTCTGTATTTCTTTAAAT (SEQ ID NO: 2059) hCV27474895 A/CGGAGGATACTGAAGTAGCAAACT (SEQ ID NO: 2062) hCV27474984 A/GACTTGAGTTACACCAGACCTA (SEQ ID NO: 2065) hCV27476043 A/G CAGGCCAGGTCAACA(SEQ ID NO: 2068) hCV27477533 A/T GAGGTTCCATGGAGTAAACAATA (SEQ ID NO:2071) hCV27480803 C/T GCACTAGAAACCTGCCG (SEQ ID NO: 2074) hCV27490984A/G CTTACTTAGGTCACTTTCAGCA (SEQ ID NO: 2077) hCV27502514 A/GATATTGGCGAGTTATCTAATGTCTT (SEQ ID NO: 2080) hCV27833944 C/TTGCTAGGGACTAACCTTGG (SEQ ID NO: 2083) hCV27878067 A/G CCCAACTGACCCAAAGGT(SEQ ID NO: 2086) hCV27902808 C/T CAGGCCTGAAGTCTAGGTC (SEQ ID NO: 2089)hCV27904396 A/G GACTACACTACTATGCAATATATCTATGTA (SEQ ID NO: 2092)hCV27937396 C/T GCCTGAATTCTGAGAAGACATAG (SEQ ID NO: 2095) hCV27956129A/C CCATTTATGCAAAAGCAGAATCA (SEQ ID NO: 2098) hCV2811695 A/CAGTGTTGTATTTGTATGTGTGTCT (SEQ ID NO: 2101) hCV2852784 G/ACACAGCTCTTCTACTCCACC (SEQ ID NO: 2104) hCV2879752 A/G GGCCTCCTGCTCCAA(SEQ ID NO: 2107) hCV2892855 C/T GGTAATCATTTAACACATTTCATGTTCC (SEQ IDNO: 2110) hCV2892869 A/G TGTGCCAGTCCTTGTGT (SEQ ID NO: 2113) hCV2892877C/T GCTCTGGACCTGGAAGTG (SEQ ID NO: 2116) hCV2892893 A/TAGTGTGCTCATGATGAAAGAAAA (SEQ ID NO: 2119) hCV2892905 C/TGTGTGATATGACTTTCATTTAGAACG (SEQ ID NO: 2122) hCV2892918 A/TTGCATCCACATAAAATGCTACT (SEQ ID NO: 2125) hCV2892926 C/TGTTCAAGTTAAATGATAGGGTAATACC (SEQ ID NO: 2128) hCV2892927 A/TGTACTTTCTGTTCAACATCTTTTAAGT (SEQ ID NO: 2131) hCV28960679 C/GCCAGACCTCATATTTTCCTTCAG (SEQ ID NO: 2134) hCV2915511 C/TCTGGCTCCTTCTCCGTC (SEQ ID NO: 2137) hCV29210363 A/GGCCATCTACAGGCTTACTCAT (SEQ ID NO: 2140) hCV29269378 A/GCATAATTTGCTTTTGACCACAACA (SEQ ID NO: 2143) hCV29271569 C/TCCAGCCTCAGGTTAAGGATC (SEQ ID NO: 2146) hCV29521317 A/GTCCATTGATACTGCATTAAACCATA (SEQ ID NO: 2149) hCV2969899 C/GGCATCCTGTCAAATACTCTCATTATAG (SEQ ID NO: 2152) hCV29821005 C/TGCAAACTAAAGCAACAATAAGACAC (SEQ ID NO: 2155) hCV2986575 A/TCCTTTGTACTTTAAATCATCTCTAGGT (SEQ ID NO: 2158) hCV29983641 A/GAGAAAATTAAGCCAGGAGAAGTTAA (SEQ ID NO: 2161) hCV30002208 A/GTGCTTTCAGGCAATTTTGAGA (SEQ ID NO: 2164) hCV30040828 C/TGGGGTGAAGAAGAAACCTCC (SEQ ID NO: 2167) hCV30205817 C/TGATGAAGTAGTTCATTTTGAATGGC (SEQ ID NO: 2170) hCV30440155 C/GCTTTGGAGTCTGCTTGTACC (SEQ ID NO: 2173) hCV30505633 C/TCGCTTAACAAAGGTGTTAGAAC (SEQ ID NO: 2176) hCV30548253 A/CGAGAGATAGAGGCAAAGGAAAAT (SEQ ID NO: 2179) hCV30562347 A/GGGCTGTCATTTCAGAAGCA (SEQ ID NO: 2182) hCV305844 C/G CTGTGCCCTTCCTGG (SEQID NO: 2185) hCV30626715 G/T AGGATGTCTGCCATTATTTCC (SEQ ID NO: 2188)hCV30690777 A/G CCGTGTGCCTGAGAAGT (SEQ ID NO: 2191) hCV30690778 C/TAGGCAGAGTTTCCACTCAG (SEQ ID NO: 2194) hCV30690780 A/CGTGTTCATTGACAGATGAGTGT (SEQ ID NO: 2197) hCV30690784 C/TAGCGATGGCCTTAGGTATC (SEQ ID NO: 2200) hCV30699692 C/TGGAAAGAACCACCTCGATATG (SEQ ID NO: 2203) hCV30711231 A/GGTGTATGTGTGTGTGTGAGAA (SEQ ID NO: 2206) hCV30922162 C/TACTGTTACTAGAGACAAGGGATAC (SEQ ID NO: 2209) hCV31056155 C/GGTTTTCTCTTTGTTACTAATATGTCACAC (SEQ ID NO: 2212) hCV31199195 A/CGAGATATCAATTGAAAACGGACATT (SEQ ID NO: 2215) hCV31475431 G/TATTGTGATTGGGGAACTTCC (SEQ ID NO: 2218) hCV31523557 A/GAGGTAGTTTGTTCCACAGCA (SEQ ID NO: 2221) hCV31523608 A/GCATTAAATGAGTTCCACTGCCT (SEQ ID NO: 2224) hCV31523638 A/GTTCTTCTGCCTCTCTCATACA (SEQ ID NO: 2227) hCV31523643 A/GTGCAAACCATGCTGGATTAA (SEQ ID NO: 2230) hCV31523650 C/TTCAACTTTTAACCAGTACTGTTCC (SEQ ID NO: 2233) hCV31523658 A/CTTGCTAATACTGCATTTCTTACAAAT (SEQ ID NO: 2236) hCV3164397 C/TTGTGCCTTACAGAATCCG (SEQ ID NO: 2239) hCV3170967 C/G GGAGGGTGAGGTCAAGC(SEQ ID NO: 2242) hCV31714450 C/T CACCTTGACCTTGGACTTC (SEQ ID NO: 2245)hCV31749285 C/T GTTGGAATTGAGGCTTATGC (SEQ ID NO: 2248) hCV3180954 A/GTCCTGGGAGCCTTTGA (SEQ ID NO: 2251) hCV31863982 A/GACAAATCCTTTGACAATCACTGT (SEQ ID NO: 2254) hCV3187716 A/CCCTTCAATTCTGAAAAGTAGCTAAT (SEQ ID NO: 2257) hCV31965333 C/TAGCCCTTCAGAAGAAAACAG (SEQ ID NO: 2260) hCV31997958 A/GCCCTGCTGGAGAAAATCA (SEQ ID NO: 2263) hCV3205858 C/TGTGCTCACTCAGAATAAAATGC (SEQ ID NO: 2266) hCV3210786 C/TCCCATGAATATTGTACTTAGGAAC (SEQ ID NO: 2269) hCV3216426 A/TTTATTTTCAGAGTCTTGAATATTATTGA (SEQ ID NO: 2272) hCV3216649 A/GCAGCTTGTACATCGTACTTAACAGT (SEQ ID NO: 2275) hCV32209605 C/TGTGAAATTACTCCTTCATCAGGG (SEQ ID NO: 2278) hCV32209620 C/TCAGGCTTTTATGTGTGCATG (SEQ ID NO: 2281) hCV32209621 A/GATGCATGTCTTGGTATTTATCCA (SEQ ID NO: 2284) hCV32212664 A/GTGATTGGAAGCATTTCCCATAAT (SEQ ID NO: 2287) hCV32291301 A/GTCAGGTTGGTCAGTGCTT (SEQ ID NO: 2290) hCV3230016 A/G AGCCAGCACAGACCATCT(SEQ ID NO: 2293) hCV3230030 A/G GGGCAAAACCCACAGTAAAA (SEQ ID NO: 2296)hCV3230038 C/T CCAGGATGAGAGGGCG (SEQ ID NO: 2299) hCV3230083 A/CCACAACTTTCTCATCTTGATTGAATTTA (SEQ ID NO: 2302) hCV3230084 C/TGAGAATCTCACCAGAATCAATATAAC (SEQ ID NO: 2305) hCV3230096 C/TAGAAGCATGTGATTATCATTCAAATC (SEQ ID NO: 2308) hCV3230099 C/TACGCCAATGAAGACTGC (SEQ ID NO: 2311) hCV3230113 A/TAAATGAAGACTATAAGTGCACGAT (SEQ ID NO: 2314) hCV3230119 C/GGCCACTACTTGGTTATTTTCTGG (SEQ ID NO: 2317) hCV3230131 C/TCCGGTGTTGTTTCAGCATAC (SEQ ID NO: 2320) hCV3230136 A/GCTAATTATGTCCACAGCCACTAT (SEQ ID NO: 2323) hCV3272537 A/TAATTTGACACTAGTCATAGCCAT (SEQ ID NO: 2326) hCV356522 C/TACCAAGCATGAACAGGATATATTAC (SEQ ID NO: 2329) hCV4041 C/TAAGTCCATCACATCTCCCC (SEQ ID NO: 2332) hCV470708 G/T CAACCCTCATTCCAGCTC(SEQ ID NO: 2335) hCV491830 C/T TCCAGCAGCCGCAG (SEQ ID NO: 2338)hCV505733 A/G ACACGGTGGCATAAGCA (SEQ ID NO: 2341) hCV540410 A/TACTCACTCTGACTTCAGTTTCTTAT (SEQ ID NO: 2344) hCV596326 A/GCCCTGAATTTGACTATATTGATTACATC (SEQ ID NO: 2347) hCV596330 A/CCATCCCTGAATGGAAGTCTT (SEQ ID NO: 2350) hCV596331 A/GAGTCCACATCAGGAAAATCAGT (SEQ ID NO: 2353) hCV596335 C/GCCCTGGAATAAGGTAAGAAATGAG (SEQ ID NO: 2356) hCV596336 C/TCCCAGTCTCCATCCACTTC (SEQ ID NO: 2359) hCV596337 C/GGGAAGTGCACCCTACAATTTAAG (SEQ ID NO: 2362) hCV596663 A/GCACCCTATCCTTCCTCGAT (SEQ ID NO: 2365) hCV596669 A/GGTATTTGGGACTACTTCCTGAT (SEQ ID NO: 2368) hCV7422466 A/CTGCTACAATTATGGAAACCCTAAA (SEQ ID NO: 2371) hCV7429782 A/TGCAAGAGATGTATCTCAACTACAAA (SEQ ID NO: 2374) hCV7429793 C/TGCCTTGTGCTATGGAGACC (SEQ ID NO: 2377) hCV7459627 A/G CTGAGTTGGAGGTCCAT(SEQ ID NO: 2380) hCV7504118 A/G CTCAACCAGCTTGACACT (SEQ ID NO: 2383)hCV7574127 A/G GGTCTTCTGAGATGGATAAATATTCAA (SEQ ID NO: 2386) hCV7581501C/G AACCCTCACAACCACCTTAC (SEQ ID NO: 2389) hCV7584272 A/GGACACCACCCAGCTCA (SEQ ID NO: 2392) hCV7625318 A/G ATCAGGGCATCGGAGT (SEQID NO: 2395) hCV788647 A/G GCACATGGCATGATTCTATTTAT (SEQ ID NO: 2398)hCV813581 G/T GCAGCAAAATAACAGTGTGC (SEQ ID NO: 2401) hCV815038 C/TCCTGACTCAGCAATTAATAGTCG (SEQ ID NO: 2404) hCV8241630 A/GCATCTCTACAAAGCTAAATCAGACAT (SEQ ID NO: 2407) hCV8361354 A/CCATGGCCATCGCTCAA (SEQ ID NO: 2410) hCV837462 A/C TGGCATACTTTCGATATACTCA(SEQ ID NO: 2413) hCV8598986 C/T GACTGTGGTGTCTGAAACTC (SEQ ID NO: 2416)hCV8688111 C/G AGAACTTGGGGATTTTCCATAC (SEQ ID NO: 2419) hCV8703249 G/TCTTTTATGGATCTTTCTAGTCTTGTTTC (SEQ ID NO: 2422) hCV8717752 A/GCCGGCTCCATCACCA (SEQ ID NO: 2425) hCV8717873 A/G AACAGAACCACCTTCCT (SEQID NO: 2428) hCV8717893 A/G GACAGTTCGGTGAAGTGA (SEQ ID NO: 2431)hCV8717916 A/C ATGAGAAGAAGGCCTTTCTT (SEQ ID NO: 2434) hCV8717949 A/CGTCGTAAGTCTCTCCTCTCTTA (SEQ ID NO: 2437) hCV8726802 A/GCCAATAAAAGTGACTCTCAGCA (SEQ ID NO: 2440) hCV8727391 G/AGGAGCTTCTTCATTTACCTTC (SEQ ID NO: 2443) hCV8827309 C/TCTTTCTCAGCAAGAGCAC (SEQ ID NO: 2446) hCV8856223 C/GAGACATTTTCTCAAGATCATGGC (SEQ ID NO: 2449) hCV8857351 C/TGATAGATAGATAGATAGATAGAGATTTTGAGG (SEQ ID NO: 2452) hCV8911768 C/TGAAAGCAGGGTGAGACTG (SEQ ID NO: 2455) hCV8919442 T/CAAGTCAAGAACATGCTAAGCA (SEQ ID NO: 2458) hCV8919444 C/TTGGTGCTGGAGAATTCAG (SEQ ID NO: 2461) hCV8919450 A/G TCCGAAACTCATCATTGAAT(SEQ ID NO: 2464) hCV8919451 A/G GATGAGTTTCGGAATGACCTA (SEQ ID NO: 2467)hCV8941510 A/C TGGTAGGGTGAACCGGA (SEQ ID NO: 2470) hCV8957432 C/GCCATTTCTTAAGACTTTCTGCTG (SEQ ID NO: 2473) hCV9102827 C/TGTAAGGGATGAGAAGGATG (SEQ ID NO: 2476) hCV9114656 C/TCCATCACTGGAGTATTTTTAGTTATAC (SEQ ID NO: 2479) hCV916106 A/GACATCACAAGCATAGCAAAGATAT (SEQ ID NO: 2482) hCV916107 C/TAGAATCCGAGAAGTCTGATG (SEQ ID NO: 2485) hCV926518 G/TGAGTTAACGTGGACATGAAGTAG (SEQ ID NO: 2488) hCV9327878 C/GTCATGAATGTCCATTTCTGG (SEQ ID NO: 2491) hCV9493081 C/T GGCAGTAGTGCGGTTG(SEQ ID NO: 2494) hCV949676 C/T CATTAGCCTGGGAAATAAATAAC (SEQ ID NO:2497) hCV9596963 A/G TGCCCCCAGCCAGAA (SEQ ID NO: 2500) hCV9680592 A/GTTGTACATGAAAATACAGGATTACA (SEQ ID NO: 2503) hCV97631 G/TCACAGGCAGCAGATTCTC (SEQ ID NO: 2506) hCV9860072 A/C GCATAGACACCATGTTCCCT(SEQ ID NO: 2509) hDV70662128 A/G AAGAGACCATATCAGAGGCAA (SEQ ID NO:2512) hDV70683187 C/G AATTTTCAAAGTTCCTTCTCTAGAATC (SEQ ID NO: 2515)hDV70683212 C/G CCCGCAATGAACTTTAATTCTG (SEQ ID NO: 2518) hDV70683382 C/GAGAATGTTTTCCTCCAGTTCAC (SEQ ID NO: 2521) hDV70941043 A/GGAAGAAATACTTGACTTGAAGAGAAATT (SEQ ID NO: 2524) hDV70965621 A/GGCTCCCGTTCCACTCT (SEQ ID NO: 2527) hDV71075942 T/G CAGCCAAGGGGTACCA (SEQID NO: 2530) hDV76976792 C/T CAATTTAAGCCAGAATCAGGTAAAC (SEQ ID NO: 2533)hDV76976795 A/G AAAGTGGACAAAGCAGTGAT (SEQ ID NO: 2536) hCV1841974 A/GGAAGCCCACCTATGCCT (SEQ ID NO: 2539) hCV1952126 A/C TCGGTCTCCTTTCTGAGTTT(SEQ ID NO: 2542) hCV22272816 A/G TCTGTTCCACCACCTCTT (SEQ ID NO: 2545)hCV25597241 A/G GACAGAGGCAGAGAGAGAA (SEQ ID NO: 2548) hCV30500334 A/GACGCATCTACTTTCTGTCTGTATA (SEQ ID NO: 2551) hCV30747430 C/TGGAAACTTCTCTTTGGGACTC (SEQ ID NO: 2554) Marker Primer 2 (Allele-specificPrimer) hCV10008773 CACGTGTGCTCACTTACAGAC (SEQ ID NO: 1589) hCV11342584GGCTGCTAGCCAAATACTATTT (SEQ ID NO: 1592) hCV11466393GGATGGAATGTTTTCCCTAAG (SEQ ID NO: 1595) hCV11503414GTTTCCTAAGACTAGATACATGGTAC (SEQ ID NO: 1598) hCV11503431CCAGTGCTTGCCTTCTT (SEQ ID NO: 1601) hCV11503469 CAGTTTACAATCTAATGCAGTGGA(SEQ ID NO: 1604) hCV11503470 CAAAATGATGGGAAGTTAGGA (SEQ ID NO: 1607)hCV11541681 CCACCTTCTCTTCAGATTCAG (SEQ ID NO: 1610) hCV11559107GAGATTTTGAAGACATCTGGTG (SEQ ID NO: 1613) hCV11629656GCCCCAATAAAAGGACACAGTTAT (SEQ ID NO: 1616) hCV11629657TGTCCTAAGATTAGCTAATATTTAACAC (SEQ ID NO: 1619) hCV11633415CCCAGAGGTCTACTATCTGAT (SEQ ID NO: 1622) hCV11726971 GCAAGGTGTCTCCGAATTAC(SEQ ID NO: 1625) hCV11786147 ACGTGCGTGAATTGAATGT (SEQ ID NO: 1628)hCV11786258 TGGAGAATACCCACTCAGC (SEQ ID NO: 1631) hCV11853483CACACACATCTTTAAAATCCATTCTATC (SEQ ID NO: 1634) hCV11853496CCTTTCTCACCTGATAGAATGAGA (SEQ ID NO: 1637) hCV11922386 CCTGGCCCTTTCCTACA(SEQ ID NO: 1640) hCV11942562 CGAATGTGATGGCCACG (SEQ ID NO: 1643)hCV11962159 CATTAAGCAACTGGTTTCCA (SEQ ID NO: 1646) hCV11975250AGGACAAAATACCTGTATTCCTC (SEQ ID NO: 1649) hCV11975296CAGTCCATGGTTCCTTCAC (SEQ ID NO: 1652) hCV11975651 ACCTTCCCCACTCTCTTAC(SEQ ID NO: 1655) hCV11975658 GGTGACAGGGGAGAAAAGG (SEQ ID NO: 1658)hCV1198623 CCATGCCTGATACAGAAGAG (SEQ ID NO: 1661) hCV1202883GCGTGATGATGAAATCGA (SEQ ID NO: 1664) hCV12066124 GCAGCTTTTGCCAGTAAAGAT(SEQ ID NO: 1667) hCV12073840 AACGGACACTGGACATACT (SEQ ID NO: 1670)hCV12086148 TGAAGGTTTCCCTTTAAGTTACC (SEQ ID NO: 1673) hCV12092542CCTTGTCTTCAATTTTGGC (SEQ ID NO: 1676) hCV12098639 GGATGTGGCTTCCCG (SEQID NO: 1679) hCV134275 GGTGCTTAGAATACATCAACAAAAC (SEQ ID NO: 1682)hCV134278 GTAACCTGATCCATTATCCAAGATAT (SEQ ID NO: 1685) hCV1376206AAGCAGGCTACTACTCCTTT (SEQ ID NO: 1688) hCV1376207 CGTACAGACAGCCGAGC (SEQID NO: 1691) hCV1376227 TCTCAACTTGGCTATCTTACAAATC (SEQ ID NO: 1694)hCV1376246 TTATTGAGTTCATCATTAAAGTCATCG (SEQ ID NO: 1697) hCV1376342TACTCACCAGTTGTGAAGACTTT (SEQ ID NO: 1700) hCV1420741 CAGGCTTTAAGGACAGGG(SEQ ID NO: 1703) hCV1455329 TGTTTTGTGAACAAAGATTCCAC (SEQ ID NO: 1706)hCV1547677 GTGACAGTCCCAACACC (SEQ ID NO: 1709) hCV15755949ATACTTAGTTCTCCCCTCCATAG (SEQ ID NO: 1712) hCV15793897AGCTCTGAGTGCACTGTGTC (SEQ ID NO: 1715) hCV15860433ACCCAAGACTTAGTAAACATTCAA (SEQ ID NO: 1718) hCV15864094TGGATCAAGCTTCGTTGTTAC (SEQ ID NO: 1721) hCV15871021GAAATCTTGCTCTTTATGAGTATTTA (SEQ ID NO: 1724) hCV15885425TTTACAATGTAACAGCAAAACCC (SEQ ID NO: 1727) hCV15947925 GCTCCAGGACAGAGAACA(SEQ ID NO: 1730) hCV15949414 GCTTTCATAATGCAAATGC (SEQ ID NO: 1733)hCV15952952 AAAGTGGAGAAGGCTCTGAC (SEQ ID NO: 1736) hCV15953063TGGAAATAATGTAGGATGAAGACG (SEQ ID NO: 1739) hCV15956034ACTGAGCTGAAATGATCCATC (SEQ ID NO: 1742) hCV15956054 CACCCAGTGCAGATTCAT(SEQ ID NO: 1745) hCV15956055 GCAAGAAGGCAAGTCCA (SEQ ID NO: 1748)hCV15956059 TGTAGTTGAAGGACAGAGTGA (SEQ ID NO: 1751) hCV15956077ACTCTAACACAGGGTTCCG (SEQ ID NO: 1754) hCV15968043 GCCCAGTTTCAAACAGGT(SEQ ID NO: 1757) hCV15977624 TCCTCTTCACCAAGGAGC (SEQ ID NO: 1760)hCV15990789 TGAACCTGAGCGTGTCAG (SEQ ID NO: 1763) hCV16000557AACAAAGTCACACCGAATCA (SEQ ID NO: 1766) hCV1605386 GTGGGAAACACACAGAAATTTG(SEQ ID NO: 1769) hCV16135173 GGCAACCTCAACACAGAG (SEQ ID NO: 1772)hCV16170613 AGCAGGCATTGTTTTCC (SEQ ID NO: 1775) hCV16172935GGAGTTACACCCATAAACCAC (SEQ ID NO: 1778) hCV16177220CATCTGGTGGTCATTCAAATA (SEQ ID NO: 1781) hCV16180170 GGGAGAGCACTTGAAATGAT(SEQ ID NO: 1784) hCV1650632 ATTCATCCAGCCACTCT (SEQ ID NO: 1787)hCV1678674 GGCTTCAAAGTGATAAATTCTATATTCA (SEQ ID NO: 1790) hCV1678682GGACACAACTCATTATTCTGGT (SEQ ID NO: 1793) hCV1703855AAACGAATGGCATGTATTTTATGA (SEQ ID NO: 1796) hCV1703867CGATGATTTTGTTCTCATGTTCA (SEQ ID NO: 1799) hCV1703892CCTGTTGCATTCTGGATACA (SEQ ID NO: 1802) hCV1703910ACCTATGTAACACACCCTTCTATC (SEQ ID NO: 1805) hCV1723643 CCCTCACAGCTCTGAAGC(SEQ ID NO: 1808) hCV1825046 CTGCACAGTCCCCTGAT (SEQ ID NO: 1811)hCV1833991 GGGAGCCTTAATAAGATTAACAGT (SEQ ID NO: 1814) hCV1834242CCTACTTTCACAAACATATCTTTGAG (SEQ ID NO: 1817) hCV1841975GTCGTGGAGATACTGCAAGTA (SEQ ID NO: 1820) hCV1842260 GTCTCAGGCACCTGGATTAT(SEQ ID NO: 1823) hCV1859855 GGCCTCACTAGAGAAGGAGAA (SEQ ID NO: 1826)hCV1874482 AAAGGTTTCTTCTGATCACTGAC (SEQ ID NO: 1829) hCV18996TGAAGTAATACTGGAGATCAAATTAT (SEQ ID NO: 1832) hCV1900162AACCAGTATACCTAGAGCATAGTGA (SEQ ID NO: 1835) hCV1937195 CAGGGCACAGATAACC(SEQ ID NO: 1838) hCV1974936 GTGTGCACAAAGATAGGTCAT (SEQ ID NO: 1841)hCV1974951 CGGGACACCATCCACG (SEQ ID NO: 1844) hCV1974967ACATCCAACGAGAAATTGCTG (SEQ ID NO: 1847) hCV2017876 CTGCTTCCAGAAGATCAAGC(SEQ ID NO: 1850) hCV2086329 CCAGCCACACTGTTGG (SEQ ID NO: 1853)hCV2103346 GAGGAGCCATGATGCCT (SEQ ID NO: 1856) hCV2103392CCTCCTCCATGAAGCTGTT (SEQ ID NO: 1859) hCV2144411 GCTCCGGGGTTATTGC (SEQID NO: 1862) hCV2211618 GGCCATGTGCTGCCATG (SEQ ID NO: 1865) hCV22272267CTGGCAGCGAATGTTAC (SEQ ID NO: 1868) hCV2288095TGAGTTAATATTTGTGTAAAGTATGATGTTTAA (SEQ ID NO: 1871) hCV2303891ACACAGTTCTCTGGCTTTTTC (SEQ ID NO: 1874) hCV233148TCATCACAGGACATTTATGAGAAC (SEQ ID NO: 1877) hCV2403368AAAGGTGAGCTCCACCATAG (SEQ ID NO: 1880) hCV2456747CCTCCACTAGAAGACACTACTACTTC (SEQ ID NO: 1883) hCV2494846ACTTCTTCCCTTCGCTCTT (SEQ ID NO: 1886) hCV2532034 CTGAAGCGCAACCATAAT (SEQID NO: 1889) hCV25473516 CACCCAATGCCAAGC (SEQ ID NO: 1892) hCV25474413GCATTCACAGTGTTCTCATTATAAG (SEQ ID NO: 1895) hCV25474414TCTGCAGAGCTGTAAGAGTT (SEQ ID NO: 1898) hCV25596789 ATCTGCTCCATTTTTCTCATC(SEQ ID NO: 1901) hCV25602230 GAAGCTGAGGAGAGTCCT (SEQ ID NO: 1904)hCV25611352 AATAATTGTAACTCTAGAACAAAAGTATTT (SEQ ID NO: 1907) hCV25615302GGTTCCAGTTCCGATAGT (SEQ ID NO: 1910) hCV25620145 CACCAGCAATGATGAAACC(SEQ ID NO: 1913) hCV25634754 AGTCACTTATTTGAATCCCATTGT (SEQ ID NO: 1916)hCV25649928 GAAGACTTTTTCCAGGAATGT (SEQ ID NO: 1919) hCV25748719CGGCAGCCAATGACAC (SEQ ID NO: 1922) hCV2575036 CAGTTTATGCCTGCAACAAC (SEQID NO: 1925) hCV25752810 GCCCATAAGGAGACAGAAAAT (SEQ ID NO: 1928)hCV25767872 CACCATGTGTGTGTTCCAC (SEQ ID NO: 1931) hCV25768636AATTTGGCCACAAAGAGC (SEQ ID NO: 1934) hCV2590858 AGAGTGAGAATTCTGTCAAGAGA(SEQ ID NO: 1937) hCV25932979 AAAGAGGGAGTAAACAACTGC (SEQ ID NO: 1940)hCV25951992 TGGAAAGATGGAGGCAG (SEQ ID NO: 1943) hCV25959466GCGATTCCTCAGCAGC (SEQ ID NO: 1946) hCV25959498 ACAACATAAAACTGACTTGGAAA(SEQ ID NO: 1949) hCV25990131 TGTTGGTAAAAGTATGTAGGATCTG (SEQ ID NO:1952) hCV25991132 CAGGAATGGAGACCATCC (SEQ ID NO: 1955) hCV25995678TCTGTCTTCCACAACCAAAA (SEQ ID NO: 1958) hCV25996277ACTATCTCCTTCAAAGGATGCT (SEQ ID NO: 1961) hCV26034142CAACCTAATTTAAGCCATCATTAACA (SEQ ID NO: 1964) hCV26034157CAACTCAAACAGGACACTGAA (SEQ ID NO: 1967) hCV26038139 CAGCTGGCGAAGTTGG(SEQ ID NO: 1970) hCV2605707 GCTGTTAATTCAGGAGGTAAAGG (SEQ ID NO: 1973)hCV26175114 CCAGTCATCTCTGCAGAAAAG (SEQ ID NO: 1976) hCV26265231GGATAAATATTACAAACCCATGCTG (SEQ ID NO: 1979) hCV26338456ACAGAAGATACAGCAAATGGAG (SEQ ID NO: 1982) hCV26338482CAAACAGTAACAGGCTCAGT (SEQ ID NO: 1985) hCV26338512 CAGGCCTCGGAAAATGAG(SEQ ID NO: 1988) hCV26338513 CGCACTTTTAGTGGCTGA (SEQ ID NO: 1991)hCV263841 AAGCTAATACTCCTGTCCTGAAC (SEQ ID NO: 1994) hCV26719108GGCAGGGGCATTGGTA (SEQ ID NO: 1997) hCV26719113CTTACGATTAGTTCCAACATGAATAT (SEQ ID NO: 2000) hCV26719121CCCACTAAGCACAGGAAAA (SEQ ID NO: 2003) hCV26719154 ATGGTCTGTGCCCTCAA (SEQID NO: 2006) hCV26719227 TGCCTTGGATATGCTTTAAAGAG (SEQ ID NO: 2009)hCV26887403 AGCACTGGAACGATAATAAAGC (SEQ ID NO: 2012) hCV26887434CTTTACGACTAATTAGGTATAAAGGTTC (SEQ ID NO: 2015) hCV26887464GCAGGTCAGATAACTTCTTTATGG (SEQ ID NO: 2018) hCV26895255ACACCGTATTCAGCTGAGAT (SEQ ID NO: 2021) hCV2699725 GTACCTCTTGGTCTCTCTCG(SEQ ID NO: 2024) hCV27020269 CCAGTTTTGCACATTTAAAGATACC (SEQ ID NO:2027) hCV2706410 CCTCCATGTCATCCTACA (SEQ ID NO: 2030) hCV27102953ATTTAGTGTAATGGGCAAGACA (SEQ ID NO: 2033) hCV27102978 CTCCTCCTGTCTCCGTG(SEQ ID NO: 2036) hCV27103080 TGGGATGTGCAACCCT (SEQ ID NO: 2039)hCV27103182 GGCATCTCTCAATCCCTACA (SEQ ID NO: 2042) hCV27103188GTTTGGACAATGACTTGGAAAC (SEQ ID NO: 2045) hCV27103189AGAGGTCAAGCCAATGAAAC (SEQ ID NO: 2048) hCV27103207 GGCTGCCAGGGACAC (SEQID NO: 2051) hCV2716314 GGCATACAAATTCAAAATACTGTATC (SEQ ID NO: 2054)hCV2734332 GCCATGTTGACTCGAGAAC (SEQ ID NO: 2057) hCV2744023CTACCTGTGTCTGTATTTCTTTAAAC (SEQ ID NO: 2060) hCV27474895GAGGATACTGAAGTAGCAAACG (SEQ ID NO: 2063) hCV27474984CTTGAGTTACACCAGACCTG (SEQ ID NO: 2066) hCV27476043 CAGGCCAGGTCAACG (SEQID NO: 2069) hCV27477533 GAGGTTCCATGGAGTAAACAATT (SEQ ID NO: 2072)hCV27480803 TGCACTAGAAACCTGCCA (SEQ ID NO: 2075) hCV27490984CTTACTTAGGTCACTTTCAGCG (SEQ ID NO: 2078) hCV27502514ATTGGCGAGTTATCTAATGTCTC (SEQ ID NO: 2081) hCV27833944CTGCTAGGGACTAACCTTGA (SEQ ID NO: 2084) hCV27878067 CCAACTGACCCAAAGGC(SEQ ID NO: 2087) hCV27902808 CAGGCCTGAAGTCTAGGTT (SEQ ID NO: 2090)hCV27904396 ACTACACTACTATGCAATATATCTATGTG (SEQ ID NO: 2093) hCV27937396GCCTGAATTCTGAGAAGACATAA (SEQ ID NO: 2096) hCV27956129CCATTTATGCAAAAGCAGAATCC (SEQ ID NO: 2099) hCV2811695GTGTTGTATTTGTATGTGTGTCG (SEQ ID NO: 2102) hCV2852784CCACAGCTCTTCTACTCCACT (SEQ ID NO: 2105) hCV2879752 GGCCTCCTGCTCCAG (SEQID NO: 2108) hCV2892855 GGTAATCATTTAACACATTTCATGTTCT (SEQ ID NO: 2111)hCV2892869 GTGCCAGTCCTTGTGC (SEQ ID NO: 2114) hCV2892877GAGCTCTGGACCTGGAAGTA (SEQ ID NO: 2117) hCV2892893AGTGTGCTCATGATGAAAGAAAT (SEQ ID NO: 2120) hCV2892905CGTGTGATATGACTTTCATTTAGAACA (SEQ ID NO: 2123) hCV2892918TGCATCCACATAAAATGCTACA (SEQ ID NO: 2126) hCV2892926GTTCAAGTTAAATGATAGGGTAATACT (SEQ ID NO: 2129) hCV2892927GTACTTTCTGTTCAACATCTTTTAAGA (SEQ ID NO: 2132) hCV28960679CCAGACCTCATATTTTCCTTCAC (SEQ ID NO: 2135) hCV2915511 CTGGCTCCTTCTCCGTT(SEQ ID NO: 2138) hCV29210363 GCCATCTACAGGCTTACTCAC (SEQ ID NO: 2141)hCV29269378 ATTTGCTTTTGACCACAACG (SEQ ID NO: 2144) hCV29271569CCAGCCTCAGGTTAAGGATT (SEQ ID NO: 2147) hCV29521317CCATTGATACTGCATTAAACCATG (SEQ ID NO: 2150) hCV2969899GCATCCTGTCAAATACTCTCATTATAC (SEQ ID NO: 2153) hCV29821005GCAAACTAAAGCAACAATAAGACAT (SEQ ID NO: 2156) hCV2986575CCTTTGTACTTTAAATCATCTCTAGGA (SEQ ID NO: 2159) hCV29983641AGAAAATTAAGCCAGGAGAAGTTAG (SEQ ID NO: 2162) hCV30002208GCTTTCAGGCAATTTTGAGG (SEQ ID NO: 2165) hCV30040828 GGGGTGAAGAAGAAACCTCT(SEQ ID NO: 2168) hCV30205817 GATGAAGTAGTTCATTTTGAATGGT (SEQ ID NO:2171) hCV30440155 CTTTGGAGTCTGCTTGTACG (SEQ ID NO: 2174) hCV30505633ACGCTTAACAAAGGTGTTAGAAT (SEQ ID NO: 2177) hCV30548253GAGAGATAGAGGCAAAGGAAAAG (SEQ ID NO: 2180) hCV30562347GGCTGTCATTTCAGAAGCG (SEQ ID NO: 2183) hCV305844 CTGTGCCCTTCCTGC (SEQ IDNO: 2186) hCV30626715 CAGGATGTCTGCCATTATTTCA (SEQ ID NO: 2189)hCV30690777 CGTGTGCCTGAGAAGC (SEQ ID NO: 2192) hCV30690778AGGCAGAGTTTCCACTCAA (SEQ ID NO: 2195) hCV30690780 TGTTCATTGACAGATGAGTGG(SEQ ID NO: 2198) hCV30690784 AGCGATGGCCTTAGGTATT (SEQ ID NO: 2201)hCV30699692 GGGAAAGAACCACCTCGATATA (SEQ ID NO: 2204) hCV30711231GTGTATGTGTGTGTGTGAGAG (SEQ ID NO: 2207) hCV30922162AACTGTTACTAGAGACAAGGGATAT (SEQ ID NO: 2210) hCV31056155GTTTTCTCTTTGTTACTAATATGTCACAG (SEQ ID NO: 2213) hCV31199195GAGATATCAATTGAAAACGGACATG (SEQ ID NO: 2216) hCV31475431GTATTGTGATTGGGGAACTTCA (SEQ ID NO: 2219) hCV31523557 GGTAGTTTGTTCCACAGCG(SEQ ID NO: 2222) hCV31523608 TTAAATGAGTTCCACTGCCC (SEQ ID NO: 2225)hCV31523638 TCTTCTGCCTCTCTCATACG (SEQ ID NO: 2228) hCV31523643TGCAAACCATGCTGGATTAG (SEQ ID NO: 2231) hCV31523650CTCAACTTTTAACCAGTACTGTTCT (SEQ ID NO: 2234) hCV31523658TGCTAATACTGCATTTCTTACAAAG (SEQ ID NO: 2237) hCV3164397CTTGTGCCTTACAGAATCCA (SEQ ID NO: 2240) hCV3170967 GGAGGGTGAGGTCAAGG (SEQID NO: 2243) hCV31714450 CACCTTGACCTTGGACTTT (SEQ ID NO: 2246)hCV31749285 GGTTGGAATTGAGGCTTATGT (SEQ ID NO: 2249) hCV3180954CCTGGGAGCCTTTGG (SEQ ID NO: 2252) hCV31863982 CAAATCCTTTGACAATCACTGC(SEQ ID NO: 2255) hCV3187716 CCTTCAATTCTGAAAAGTAGCTAAG (SEQ ID NO: 2258)hCV31965333 CAGCCCTTCAGAAGAAAACAA (SEQ ID NO: 2261) hCV31997958CCCTGCTGGAGAAAATCG (SEQ ID NO: 2264) hCV3205858 AGTGCTCACTCAGAATAAAATGT(SEQ ID NO: 2267) hCV3210786 CCCATGAATATTGTACTTAGGAAT (SEQ ID NO: 2270)hCV3216426 GTTATTTTCAGAGTCTTGAATATTATTGT (SEQ ID NO: 2273) hCV3216649GCTTGTACATCGTACTTAACAGC (SEQ ID NO: 2276) hCV32209605GTGAAATTACTCCTTCATCAGGA (SEQ ID NO: 2279) hCV32209620TTCAGGCTTTTATGTGTGCATA (SEQ ID NO: 2282) hCV32209621TGCATGTCTTGGTATTTATCCG (SEQ ID NO: 2285) hCV32212664GATTGGAAGCATTTCCCATAAC (SEQ ID NO: 2288) hCV32291301 TCAGGTTGGTCAGTGCTC(SEQ ID NO: 2291) hCV3230016 GCCAGCACAGACCATCC (SEQ ID NO: 2294)hCV3230030 GGGCAAAACCCACAGTAAAG (SEQ ID NO: 2297) hCV3230038CCAGGATGAGAGGGCA (SEQ ID NO: 2300) hCV3230083ACAACTTTCTCATCTTGATTGAATTTC (SEQ ID NO: 2303) hCV3230084TGAGAATCTCACCAGAATCAATATAAT (SEQ ID NO: 2306) hCV3230096CAGAAGCATGTGATTATCATTCAAATT (SEQ ID NO: 2309) hCV3230099GAACGCCAATGAAGACTGT (SEQ ID NO: 2312) hCV3230113AAATGAAGACTATAAGTGCACGAA (SEQ ID NO: 2315) hCV3230119GCCACTACTTGGTTATTTTCTGC (SEQ ID NO: 2318) hCV3230131CCGGTGTTGTTTCAGCATAT (SEQ ID NO: 2321) hCV3230136CTAATTATGTCCACAGCCACTAC (SEQ ID NO: 2324) hCV3272537AATTTGACACTAGTCATAGCCAA (SEQ ID NO: 2327) hCV356522ACCAAGCATGAACAGGATATATTAT (SEQ ID NO: 2330) hCV4041 GAAGTCCATCACATCTCCCT(SEQ ID NO: 2333) hCV470708 CAACCCTCATTCCAGCTA (SEQ ID NO: 2336)hCV491830 TCCAGCAGCCGCAA (SEQ ID NO: 2339) hCV505733 CACGGTGGCATAAGCG(SEQ ID NO: 2342) hCV540410 ACTCACTCTGACTTCAGTTTCTTAA (SEQ ID NO: 2345)hCV596326 CCTGAATTTGACTATATTGATTACATCG (SEQ ID NO: 2348) hCV596330CATCCCTGAATGGAAGTCTG (SEQ ID NO: 2351) hCV596331 GTCCACATCAGGAAAATCAGC(SEQ ID NO: 2354) hCV596335 CCCTGGAATAAGGTAAGAAATGAC (SEQ ID NO: 2357)hCV596336 CCCAGTCTCCATCCACTTT (SEQ ID NO: 2360) hCV596337GGAAGTGCACCCTACAATTTAAC (SEQ ID NO: 2363) hCV596663 CACCCTATCCTTCCTCGAC(SEQ ID NO: 2366) hCV596669 GTATTTGGGACTACTTCCTGAC (SEQ ID NO: 2369)hCV7422466 TGCTACAATTATGGAAACCCTAAC (SEQ ID NO: 2372) hCV7429782GCAAGAGATGTATCTCAACTACAAT (SEQ ID NO: 2375) hCV7429793GCCTTGTGCTATGGAGACT (SEQ ID NO: 2378) hCV7459627 CTGAGTTGGAGGTCCAC (SEQID NO: 2381) hCV7504118 CTCAACCAGCTTGACACC (SEQ ID NO: 2384) hCV7574127GGTCTTCTGAGATGGATAAATATTCAG (SEQ ID NO: 2387) hCV7581501AACCCTCACAACCACCTTAG (SEQ ID NO: 2390) hCV7584272 ACACCACCCAGCTCG (SEQID NO: 2393) hCV7625318 CAGGGCATCGGAGC (SEQ ID NO: 2396) hCV788647GCACATGGCATGATTCTATTTAC (SEQ ID NO: 2399) hCV813581TGCAGCAAAATAACAGTGTGA (SEQ ID NO: 2402) hCV815038CCTGACTCAGCAATTAATAGTCA (SEQ ID NO: 2405) hCV8241630TCTCTACAAAGCTAAATCAGACAC (SEQ ID NO: 2408) hCV8361354 CATGGCCATCGCTCAC(SEQ ID NO: 2411) hCV837462 TGGCATACTTTCGATATACTCC (SEQ ID NO: 2414)hCV8598986 GACTGTGGTGTCTGAAACTT (SEQ ID NO: 2417) hCV8688111AAGAACTTGGGGATTTTCCATAG (SEQ ID NO: 2420) hCV8703249CTTTTATGGATCTTTCTAGTCTTGTTTA (SEQ ID NO: 2423) hCV8717752CCGGCTCCATCACCG (SEQ ID NO: 2426) hCV8717873 ACAGAACCACCTTCCC (SEQ IDNO: 2429) hCV8717893 GACAGTTCGGTGAAGTGG (SEQ ID NO: 2432) hCV8717916TGAGAAGAAGGCCTTTCTG (SEQ ID NO: 2435) hCV8717949 TCGTAAGTCTCTCCTCTCTTC(SEQ ID NO: 2438) hCV8726802 CAATAAAAGTGACTCTCAGCG (SEQ ID NO: 2441)hCV8727391 GGAGCTTCTTCATTTACCTTT (SEQ ID NO: 2444) hCV8827309CTTTCTCAGCAAGAGCAT (SEQ ID NO: 2447) hCV8856223 AGACATTTTCTCAAGATCATGGG(SEQ ID NO: 2450) hCV8857351 GATAGATAGATAGATAGATAGAGATTTTGAGA (SEQ IDNO: 2453) hCV8911768 GGAAAGCAGGGTGAGACTA (SEQ ID NO: 2456) hCV8919442AGTCAAGAACATGCTAAGCG (SEQ ID NO: 2459) hCV8919444 TGGTGCTGGAGAATTCAA(SEQ ID NO: 2462) hCV8919450 TCCGAAACTCATCATTGAAC (SEQ ID NO: 2465)hCV8919451 TGAGTTTCGGAATGACCTG (SEQ ID NO: 2468) hCV8941510GGTAGGGTGAACCGGC (SEQ ID NO: 2471) hCV8957432 CCATTTCTTAAGACTTTCTGCTC(SEQ ID NO: 2474) hCV9102827 TGTAAGGGATGAGAAGGATA (SEQ ID NO: 2477)hCV9114656 CCATCACTGGAGTATTTTTAGTTATAT (SEQ ID NO: 2480) hCV916106CATCACAAGCATAGCAAAGATAC (SEQ ID NO: 2483) hCV916107GAAGAATCCGAGAAGTCTGATA (SEQ ID NO: 2486) hCV926518GAGTTAACGTGGACATGAAGTAT (SEQ ID NO: 2489) hCV9327878TCATGAATGTCCATTTCTGC (SEQ ID NO: 2492) hCV9493081 TGGCAGTAGTGCGGTTA (SEQID NO: 2495) hCV949676 CATTAGCCTGGGAAATAAATAAT (SEQ ID NO: 2498)hCV9596963 TGCCCCCAGCCAGAG (SEQ ID NO: 2501) hCV9680592TGTACATGAAAATACAGGATTACG (SEQ ID NO: 2504) hCV97631 TCACAGGCAGCAGATTCTA(SEQ ID NO: 2507) hCV9860072 CATAGACACCATGTTCCCG (SEQ ID NO: 2510)hDV70662128 AGAGACCATATCAGAGGCAG (SEQ ID NO: 2513) hDV70683187AATTTTCAAAGTTCCTTCTCTAGAATG (SEQ ID NO: 2516) hDV70683212CCCGCAATGAACTTTAATTCTC (SEQ ID NO: 2519) hDV70683382AGAATGTTTTCCTCCAGTTCAG (SEQ ID NO: 2522) hDV70941043GAAGAAATACTTGACTTGAAGAGAAATC (SEQ ID NO: 2525) hDV70965621GCTCCCGTTCCACTCC (SEQ ID NO: 2528) hDV71075942 AGCCAAGGGGTCACC (SEQ IDNO: 2531) hDV76976792 CAATTTAAGCCAGAATCAGGTAAAT (SEQ ID NO: 2534)hDV76976795 AAGTGGACAAAGCAGTGAC (SEQ ID NO: 2537) hCV1841974AGCCCACCTATGCCC (SEQ ID NO: 2540) hCV1952126 TCGGTCTCCTTTCTGAGTTG (SEQID NO: 2543) hCV22272816 TCTGTTCCACCACCTCTC (SEQ ID NO: 2546)hCV25597241 GACAGAGGCAGAGAGAGAG (SEQ ID NO: 2549) hCV30500334CGCATCTACTTTCTGTCTGTATG (SEQ ID NO: 2552) hCV30747430GGAAACTTCTCTTTGGGACTT (SEQ ID NO: 2555) Marker Common Primer hCV10008773CGGCTCGATTGTCTCATAC (SEQ ID NO: 1590) hCV11342584AGACTGCAACCTGGGAAATCCTATAG (SEQ ID NO: 1593) hCV11466393CCTTCATGCATGGAAATTC (SEQ ID NO: 1596) hCV11503414CCCAAAGAGTTAGGCATAACATTTAGCAT (SEQ ID NO: 1599) hCV11503431CATGGATGCTTGTTGACACATTAACCT (SEQ ID NO: 1602) hCV11503469CTCAGCTAATCAGTTGTCAATCAAGTCA (SEQ ID NO: 1605) hCV11503470AAGCTTAGATTTGTTTTCTCACATA (SEQ ID NO: 1608) hCV11541681CTGGACGCGGTATGTAGAC (SEQ ID NO: 1611) hCV11559107 CTGAATGCAAGCTGATGACT(SEQ ID NO: 1614) hCV11629656 TGAATTTGGGAGGCACTTAG (SEQ ID NO: 1617)hCV11629657 AAGTGCCTCCCAAATTCAC (SEQ ID NO: 1620) hCV11633415CCCTCATTTTAGCATGTAGCAGTTCA (SEQ ID NO: 1623) hCV11726971TTTTGGGAGGTGATAGCCAGAATCA (SEQ ID NO: 1626) hCV11786147GCACGGACATACTCGGAATCATC (SEQ ID NO: 1629) hCV11786258GCGGGGATGGTATTCACAACATTTA (SEQ ID NO: 1632) hCV11853483CCCAATGCCTGTGCTCTTAAC (SEQ ID NO: 1635) hCV11853496TCATTGTGTGCTACTCCCACTTCA (SEQ ID NO: 1638) hCV11922386CACTGCTGGACAGCAATCTGT (SEQ ID NO: 1641) hCV11942562 GGCAGCCTGGTTGATGAGT(SEQ ID NO: 1644) hCV11962159 TCAAGCAGTGGTGATCTCAG (SEQ ID NO: 1647)hCV11975250 GATGAACCCACAGAAAATGAT (SEQ ID NO: 1650) hCV11975296CTCCACCTGCATTTCAGAG (SEQ ID NO: 1653) hCV11975651 GCCTTTTGCATGCCTTAACACT(SEQ ID NO: 1656) hCV11975658 GTCTGACCTAGGCTAATGTCTAACACT (SEQ ID NO:1659) hCV1198623 TGTGTCAGGTGGGATGAGA (SEQ ID NO: 1662) hCV1202883AGCCTCTCCTGACTGTCATC (SEQ ID NO: 1665) hCV12066124GGTACGTTGGCTTCAATGGAATTG (SEQ ID NO: 1668) hCV12073840GTGACATCAGCTCTGTGTTGAGAT (SEQ ID NO: 1671) hCV12086148CCTTCTCCCTCTTGCCTTCACT (SEQ ID NO: 1674) hCV12092542AACAGTTAAGATGTTGGAATACCT (SEQ ID NO: 1677) hCV12098639GACTCGGACCCTGACTGA (SEQ ID NO: 1680) hCV134275CCAATCTTCCTTACCCGATTTCTTCT (SEQ ID NO: 1683) hCV134278GGAGCCACCCGACACTTAC (SEQ ID NO: 1686) hCV1376206 GCAGCAATTCCTGTTTGATGTC(SEQ ID NO: 1689) hCV1376207 TCACCGGACATCAAACAGGAATTG (SEQ ID NO: 1692)hCV1376227 GCCCATCCCGAGTCAAATTCT (SEQ ID NO: 1695) hCV1376246CTGTGCCTCCTTAACAGACTTTCAG (SEQ ID NO: 1698) hCV1376342TCAGGGAGCCTAGATATCTCA (SEQ ID NO: 1701) hCV1420741 CCAGCATTCGTGGACTCAA(SEQ ID NO: 1704) hCV1455329 GGGGCACTTACACAGCTATAGACA (SEQ ID NO: 1707)hCV1547677 TGATTCTGGAATGATGGTAAGTC (SEQ ID NO: 1710) hCV15755949GGTGAAGAATGTTTGGCTCCTAGAAATA (SEQ ID NO: 1713) hCV15793897CAGAGTCTAGGCAATTTTTACAAC (SEQ ID NO: 1716) hCV15860433CCTGTACTTTATCTGGCAATCCTACCT (SEQ ID NO: 1719) hCV15864094GACCCAAGTGTCATTCTCAGTAGACA (SEQ ID NO: 1722) hCV15871021CATGTCTGAGGGTGATATTTATTC (SEQ ID NO: 1725) hCV15885425TCCACCTCTTCCCGTGAGAAAG (SEQ ID NO: 1728) hCV15947925CACCGCTTACCTCCCTTCTG (SEQ ID NO: 1731) hCV15949414 TCTTGCAGGTGGAACAGAT(SEQ ID NO: 1734) hCV15952952 CACACACACACGAAACAATACTAC (SEQ ID NO: 1737)hCV15953063 GGATCCCGGCAGTGACT (SEQ ID NO: 1740) hCV15956034CACGGGGCCTAGGATGGTATATT (SEQ ID NO: 1743) hCV15956054CGGCTTTGCACCTCTGTTCTT (SEQ ID NO: 1746) hCV15956055 GGGTCTGTGTGTGGGTACTG(SEQ ID NO: 1749) hCV15956059 GGTGCAAAGCCGGAGAGAA (SEQ ID NO: 1752)hCV15956077 CCTCTCATGGGAGATGAACAGTACA (SEQ ID NO: 1755) hCV15968043GAGAAAGGTGTATCTTTTGTAATGTCTGACAGAT (SEQ ID NO: 1758) hCV15977624CTCCCATCAGCCTAGGATCATG (SEQ ID NO: 1761) hCV15990789 GCCAGTGCCTTCCTACAA(SEQ ID NO: 1764) hCV16000557 CCCCTGCGTGATCATTAAAGTG (SEQ ID NO: 1767)hCV1605386 GCACCATTGCCCTCCAG (SEQ ID NO: 1770) hCV16135173GCCTGCTACATTTGAACTTGCTCTTA (SEQ ID NO: 1773) hCV16170613CCTATAAACAGCATGTGATCATATT (SEQ ID NO: 1776) hCV16172935GAGCAAGCTCAGAAAATTTTTAT (SEQ ID NO: 1779) hCV16177220TGATTGTGAGGTTCTAAAAGAGATA (SEQ ID NO: 1782) hCV16180170CAAAGGACTCACAGGAATGAC (SEQ ID NO: 1785) hCV1650632 CTTCAAAGGTGATGACATC(SEQ ID NO: 1788) hCV1678674 ACTATTCATAGATGCCTGTCACTATTCAGAA (SEQ ID NO:1791) hCV1678682 TGGGGAAGGCCTGATGTCA (SEQ ID NO: 1794) hCV1703855CAAGTGAAACATGGCGTCTTGT (SEQ ID NO: 1797) hCV1703867CCATCACCCAGGGATTTCAACTTAC (SEQ ID NO: 1800) hCV1703892GCTTCTACCGCTTCCCTCTACT (SEQ ID NO: 1803) hCV1703910CCTTGCATCTTCGTATACTGTTAATTCTAAACC (SEQ ID NO: 1806) hCV1723643TCCACACGCACAAGATGA (SEQ ID NO: 1809) hCV1825046CTTCGAAGAAGACATGGGCTCTAGA (SEQ ID NO: 1812) hCV1833991CCTCTCCAACATCCTCTCCTTGTTAT (SEQ ID NO: 1815) hCV1834242CTTACCATCTTTGGTTCTTGCCATCTT (SEQ ID NO: 1818) hCV1841975GCTAGTGCCACTGTTTGTCTATG (SEQ ID NO: 1821) hCV1842260TTATCCAAATTTCACCATCTCA (SEQ ID NO: 1824) hCV1859855 GGAAGGAGGCTGGTGTGT(SEQ ID NO: 1827) hCV1874482 CCCTTTTTGCAGCTGTATTC (SEQ ID NO: 1830)hCV18996 TGCTGCCCCATTTTCTAATA (SEQ ID NO: 1833) hCV1900162TGTTCTTTGGTGGGTAACTTTA (SEQ ID NO: 1836) hCV1937195 GGCCTCTTCCCTTTGATTA(SEQ ID NO: 1839) hCV1974936 AGGCTTAGACAAGGTGGTGACTTAC (SEQ ID NO: 1842)hCV1974951 TCCTCCATGCTGGGTACCTC (SEQ ID NO: 1845) hCV1974967AGGGTCCACGTCTGACAAGT (SEQ ID NO: 1848) hCV2017876TCCAGACAGCAGAGGATTACTGG (SEQ ID NO: 1851) hCV2086329CTTGCCTGCATTTTTAACAC (SEQ ID NO: 1854) hCV2103346ACTGGTGTGGTCAACGTGTATCA (SEQ ID NO: 1857) hCV2103392CCATAATGCAATGTGGCAAGTTCTAC (SEQ ID NO: 1860) hCV2144411CCCGTGTGCTTCTGTTTC (SEQ ID NO: 1863) hCV2211618 AGTGTGGCTAGCTTGCTCTATAT(SEQ ID NO: 1866) hCV22272267 CCTCTAGAAAGAAAATGGACTGTAT (SEQ ID NO:1869) hCV2288095 CGAGGAAGGATAGGGTGGTATTGT (SEQ ID NO: 1872) hCV2303891TGGATGAACAAGAAACAAGTGT (SEQ ID NO: 1875) hCV233148 CCGCTGACAATCACAGTGTT(SEQ ID NO: 1878) hCV2403368 GGCATCGGCACATAGTAGA (SEQ ID NO: 1881)hCV2456747 TTCTTCACAGCTTCCATTAGTAAG (SEQ ID NO: 1884) hCV2494846CAACAGGCAGGTTTCTTCTC (SEQ ID NO: 1887) hCV2532034 TCCCATAGAAAAATGCACTAAG(SEQ ID NO: 1890) hCV25473516 GCACATGCGCAATAGC (SEQ ID NO: 1893)hCV25474413 GGCTTCTGCAGAGCTGTAAGA (SEQ ID NO: 1896) hCV25474414AAGAAATAGGGAGAGAGGGGAGTAGT (SEQ ID NO: 1899) hCV25596789TTTAAGCCTTCTACCTACAACATTAC (SEQ ID NO: 1902) hCV25602230ACGTCCGAGACACAGTC (SEQ ID NO: 1905) hCV25611352 AGAAACTTTTCTTTGCTGATGA(SEQ ID NO: 1908) hCV25615302 GGGTTGGGCTTAATGACTT (SEQ ID NO: 1911)hCV25620145 GGGCTAACTCTTTGCATGTTC (SEQ ID NO: 1914) hCV25634754GCAAACTAAGGGACCACCTGAATC (SEQ ID NO: 1917) hCV25649928TTCTTAAAGGGTCATGAAACTTAC (SEQ ID NO: 1920) hCV25748719AACCTCCAGCTTTCAGACAC (SEQ ID NO: 1923) hCV2575036 TTGGCTCTGGAGAATGAGA(SEQ ID NO: 1926) hCV25752810 AATGCAGTAATTTGTGAGTTTTACTAC (SEQ ID NO:1929) hCV25767872 AATCCAGAGCTTCAGATTCTG (SEQ ID NO: 1932) hCV25768636CCCCGCCAGACATCTT (SEQ ID NO: 1935) hCV2590858 GGTGAAGCCCACGATATCT (SEQID NO: 1938) hCV25932979 TCCCTTCTTGGACTTCACATTGATGA (SEQ ID NO: 1941)hCV25951992 GAGGGCACCAATCATTACA (SEQ ID NO: 1944) hCV25959466TGTGCTGATCAGCAAAGTGT (SEQ ID NO: 1947) hCV25959498 AATGGGCTGGCTACCAT(SEQ ID NO: 1950) hCV25990131 CCATTTATAGAATGAGTGAGATGATAT (SEQ ID NO:1953) hCV25991132 AGTAAAGGGCAGGAACATAGAG (SEQ ID NO: 1956) hCV25995678TGTGGTTGTAAGAATCAATCCTAA (SEQ ID NO: 1959) hCV25996277GCACAGAGCTTAGGAGACATAG (SEQ ID NO: 1962) hCV26034142GCAACAGGCTGATGTTCATATATTTCTCTT (SEQ ID NO: 1965) hCV26034157ATACGACGATCATGAGCCATGTCTA (SEQ ID NO: 1968) hCV26038139TGCCATGTAGCCATCTTGAGTGTA (SEQ ID NO: 1971) hCV2605707CTTGGAGGCCAGAACAATAGGTAGAA (SEQ ID NO: 1974) hCV26175114GGATCACACTTCACCATCTG (SEQ ID NO: 1977) hCV26265231TGACCCAAATCCTTTTCTCACCATACT (SEQ ID NO: 1980) hCV26338456AGGTGTTCCTGATGTCATTTCACAGTA (SEQ ID NO: 1983) hCV26338482CATCTCAAGGGTAGGGAGAAGTCAA (SEQ ID NO: 1986) hCV26338512TTTGAAACGCCCGACATTCTTCTATTC (SEQ ID NO: 1989) hCV26338513GGGCAGTACAGGACATACATTCTC (SEQ ID NO: 1992) hCV263841AAGTTCTTTGCTCCGACTTCT (SEQ ID NO: 1995) hCV26719108CCTTTACCCACCTTCCTCTGTATCT (SEQ ID NO: 1998) hCV26719113TCTTCCACCATCCCAAAGTTACTAAACA (SEQ ID NO: 2001) hCV26719121CAGTTGAAGTGGACAGGCATTACT (SEQ ID NO: 2004) hCV26719154CCTATTGCTCCCACTCTTCCTACTAC (SEQ ID NO: 2007) hCV26719227AAACATTTGCCACAAGGCAAGTTTTG (SEQ ID NO: 2010) hCV26887403CCTTGCAAATAACCATTAAGACCCTTACA (SEQ ID NO: 2013) hCV26887434GTTGCTAAATCTCCCATTTCTGCTCTTAT (SEQ ID NO: 2016) hCV26887464CTGTTCCATTCTCCCCAGAGACTA (SEQ ID NO: 2019) hCV26895255GTCTGGGGTGAATCCAGTCAT (SEQ ID NO: 2022) hCV2699725GGAGCATGTTGTGTTTCTGATTGTA (SEQ ID NO: 2025) hCV27020269GGCTCTCTGCCCCATGAAC (SEQ ID NO: 2028) hCV2706410 TGCCGAGTCTGAGAAGATTC(SEQ ID NO: 2031) hCV27102953 CACAGCCTGTATCGGTTTGAACTAAC (SEQ ID NO:2034) hCV27102978 GATTTTGGAGCTGGGTCACTCAC (SEQ ID NO: 2037) hCV27103080GTTCCAGGACAACCCTCAGATACT (SEQ ID NO: 2040) hCV27103182GCATCTGAGTTTGCCTGACACA (SEQ ID NO: 2043) hCV27103188CCTGAACCCAGGAGGTCATCT (SEQ ID NO: 2046) hCV27103189GGGGCAGATGTGAATTAGTGTCT (SEQ ID NO: 2049) hCV27103207CTGTGGTACCCCTTGGAGGAG (SEQ ID NO: 2052) hCV2716314GGTGTCTTGGTGATCTCACATAA (SEQ ID NO: 2055) hCV2734332TGTGAGGGAGGCTGTCTACT (SEQ ID NO: 2058) hCV2744023ATCTGCCTTCTTAGTGAATTGAT (SEQ ID NO: 2061) hCV27474895GAGTTCGGTATGCATCCTCACAT (SEQ ID NO: 2064) hCV27474984TCAGCCGTTCAGACAATATTGTTA (SEQ ID NO: 2067) hCV27476043CAGGACCCTCCCTCAGAGAC (SEQ ID NO: 2070) hCV27477533CATTGCCTTTTATGAGGCTCAAACATA (SEQ ID NO: 2073) hCV27480803CATCCAAGGGTATACTGTGCCATTAT (SEQ ID NO: 2076) hCV27490984GTCTGGAAACAACTCGGAGGATACT (SEQ ID NO: 2079) hCV27502514CTCACAATTGCATAGTGCCCTCTTA (SEQ ID NO: 2082) hCV27833944CAACTTGTATTCCTCTGCAGGATTTACTG (SEQ ID NO: 2085) hCV27878067CCAGAATGCAACAGGTAAATATAACATCAAATCC (SEQ ID NO: 2088) hCV27902808CCCCAGCACCAGGATTCAG (SEQ ID NO: 2091) hCV27904396ACCTTCCCCTGATTTCCTGACATAT (SEQ ID NO: 2094) hCV27937396AGGCCAATCTTAGGTTCTACAAACAGT (SEQ ID NO: 2097) hCV27956129GACATTTGGCTTGGTTCCAAGTCTT (SEQ ID NO: 2100) hCV2811695GGTTTATGAGCAGCAGGCATACA (SEQ ID NO: 2103) hCV2852784 GAGGCTCTTGGGGTACTT(SEQ ID NO: 2106) hCV2879752 TCCCAGCCCCACAAGAG (SEQ ID NO: 2109)hCV2892855 GCATCTCAGGAAATTCAGCACAACT (SEQ ID NO: 2112) hCV2892869CTGCCACTCTCGCATGTCATT (SEQ ID NO: 2115) hCV2892877 CCAGAGCCTGGGCTATCT(SEQ ID NO: 2118) hCV2892893 TTGTCCCTCATCCTTGTCATCACT (SEQ ID NO: 2121)hCV2892905 CATGGCTTCCTGTAATGGAAACACAT (SEQ ID NO: 2124) hCV2892918CATCTCCCAGCTGAGTCAACAAC (SEQ ID NO: 2127) hCV2892926GAACGATTAGAATGCTGAACTTTCACATTTAGAC (SEQ ID NO: 2130) hCV2892927CAGTGTTAATGAGTGTAGACCTCAGAGAT (SEQ ID NO: 2133) hCV28960679CGGCCTGGCTGCTAACA (SEQ ID NO: 2136) hCV2915511 GGGACTGAGGCTCCAACTAC (SEQID NO: 2139) hCV29210363 GCTGCTATAATAAAGTTGCTCCTTCAAGTA (SEQ ID NO:2142) hCV29269378 CACTCAAGTACTCAAGCCTCTTTTATAAGC (SEQ ID NO: 2145)hCV29271569 AACTCCCGACCCCAGGTAATC (SEQ ID NO: 2148) hCV29521317TCTTTGTGTTGCCTGCCTATG (SEQ ID NO: 2151) hCV2969899CACCTGAGACAGAATTGGGTCTAAC (SEQ ID NO: 2154) hCV29821005CTCCTGTTGCTTCACATCCTCTCTA (SEQ ID NO: 2157) hCV2986575ATGGTTGCATCTCTACTGAACATGTACA (SEQ ID NO: 2160) hCV29983641CCCTCCCCATTTGTTGTCATGA (SEQ ID NO: 2163) hCV30002208GAGGCCTCTGTCTTTGGTTTTGTA (SEQ ID NO: 2166) hCV30040828GACAGTGAATGGGTCAGCACATAC (SEQ ID NO: 2169) hCV30205817CCCCAACTGCAGCTCCTAAATATTATAC (SEQ ID NO: 2172) hCV30440155GGAAGATGGTGCTTGCAAAGAAGAT (SEQ ID NO: 2175) hCV30505633CAGGCAGAAGAATAAGGGTTGAA (SEQ ID NO: 2178) hCV30548253TTCATCTGGTTCTCCTCTGGATAGTCT (SEQ ID NO: 2181) hCV30562347GCCTTCAGAACAATGCCTGATACAT (SEQ ID NO: 2184) hCV305844GACCCTGAGCCCAAAGAAACT (SEQ ID NO: 2187) hCV30626715GGAGACCCAATTGATTAATGCTCATGT (SEQ ID NO: 2190) hCV30690777GCCCACAGCATACAGTAACACTA (SEQ ID NO: 2193) hCV30690778AAGGCCTATGCCCATGATTTCTACT (SEQ ID NO: 2196) hCV30690780GTACTCTTTATCTGGCTTGTTCATTTAGCA (SEQ ID NO: 2199) hCV30690784GTGTTTCCCTGTGTGTGTGATGTAT (SEQ ID NO: 2202) hCV30699692CCTCGAGGCCCACTGTTTTATAATAC (SEQ ID NO: 2205) hCV30711231TCTAAGCCATCCAGTTTGTGGTACTT (SEQ ID NO: 2208) hCV30922162CTCTGAAATCTGTCAGTTTTGTTTCATG (SEQ ID NO: 2211) hCV31056155CAAGAAATCTATCAACAGGAGCTTGGTTAT (SEQ ID NO: 2214) hCV31199195CAAGGAATCCTACCTCACCTTCTCATA (SEQ ID NO: 2217) hCV31475431GGAGTCCTGGAGAGCAGAGTC (SEQ ID NO: 2220) hCV31523557GGCAACACCCTCACAGATACAC (SEQ ID NO: 2223) hCV31523608CTGTGCACGTGGTAACTAATTGACT (SEQ ID NO: 2226) hCV31523638GGAGATTCCAATGGTGTTAGTCAATATGT (SEQ ID NO: 2229) hCV31523643GGGCCCCTTCAGTCACAGTA (SEQ ID NO: 2232) hCV31523650CGAATTCCTTAAGGGCACCTTATCTT (SEQ ID NO: 2235) hCV31523658TGACACAGAGGCACAACATAAGC (SEQ ID NO: 2238) hCV3164397GAGCAGTTGCTCTTCATCATC (SEQ ID NO: 2241) hCV3170967TCATCTTCCTCTTCCTCTGTGT (SEQ ID NO: 2244) hCV31714450CAGGGTGCTATAACAGAATGCAATAGAC (SEQ ID NO: 2247) hCV31749285GGAAGGAATGAAAGCTTTGGGTTTGA (SEQ ID NO: 2250) hCV3180954CAACCATATCCTGGTGTGTG (SEQ ID NO: 2253) hCV31863982CTGCTTTCAAACCACAAATTCATGTGT (SEQ ID NO: 2256) hCV3187716TTTGAGGTTGAGTGACATGTTC (SEQ ID NO: 2259) hCV31965333GTGCTGGAGCAATTTGGTTCAGATA (SEQ ID NO: 2262) hCV31997958CGTGTGAGGGGACAGAGAGAA (SEQ ID NO: 2265) hCV3205858 TGTGAGAGCAACAGCTTGAAT(SEQ ID NO: 2268) hCV3210786 CCTCCCTTGCTCAGTCACT (SEQ ID NO: 2271)hCV3216426 ACAGACAGTGGACAGACAATCT (SEQ ID NO: 2274) hCV3216649GCCACGTGGTAAAAATGACT (SEQ ID NO: 2277) hCV32209605CTCTTTGACAATGCAATGGTCACT (SEQ ID NO: 2280) hCV32209620GAAGCAACAGGAGCTCTCATTCAT (SEQ ID NO: 2283) hCV32209621GGTGCTTTCTAGTTTTGGCAATTATGAGT (SEQ ID NO: 2286) hCV32212664CTAGGTTCCTGGAAGCAGCTCTTAT (SEQ ID NO: 2289) hCV32291301CTTCACCGCCATGTGACTTTATGAA (SEQ ID NO: 2292) hCV3230016ATATTGGTTACTCACAGGTGAAAT (SEQ ID NO: 2295) hCV3230030GTGTTTCTGTTTAGCCTGTTAGCTATACAAA (SEQ ID NO: 2298) hCV3230038GGGATGAAGGATTGAAGGTTAGAACAATT (SEQ ID NO: 2301) hCV3230083CGGCATGTGGCGGTATTC (SEQ ID NO: 2304) hCV3230084 TCCCAGGATTCGGGCTATACC(SEQ ID NO: 2307) hCV3230096 GTCAAGAAAGGCCCTGCGTTTAT (SEQ ID NO: 2310)hCV3230099 TTCCCTTCGTCATCAGTCACACTTA (SEQ ID NO: 2313) hCV3230113GTGGGACCAGTTATGACAAGAATAATCATTATAGTAC (SEQ ID NO: 2316) hCV3230119AAACTCCCGTTCTATGATCGTTGTAGTT (SEQ ID NO: 2319) hCV3230131GAGAGGCCTGGAACCTCAGATAC (SEQ ID NO: 2322) hCV3230136CATCCTTGGAGTGAGGACCTG (SEQ ID NO: 2325) hCV3272537 TGGTGGCACACACCTATAGTC(SEQ ID NO: 2328) hCV356522 AACCCAGACTGGTTTGATATAGTATCT (SEQ ID NO:2331) hCV4041 CCGTTTTTGTTTTTTGTTTTGTA (SEQ ID NO: 2334) hCV470708AGTGCTGGAGCCAAGATAAC (SEQ ID NO: 2337) hCV491830 CCTGGCCACATTCATCAT (SEQID NO: 2340) hCV505733 TGATCTGACTCCAAGCTGAGTTTAC (SEQ ID NO: 2343)hCV540410 TGTACTGAATGGTGTCATTTACTC (SEQ ID NO: 2346) hCV596326ACTGGGGTTTACTGCTCCAATTACT (SEQ ID NO: 2349) hCV596330CCTTGGAATCTAGAAGGCCTTTTAGTCT (SEQ ID NO: 2352) hCV596331CCATTTGCCAATGAGAAATATCAGGTTACT (SEQ ID NO: 2355) hCV596335GTTCACCTGGCCAGAGATCAGA (SEQ ID NO: 2358) hCV596336CTTTGCATGTTATCTGCCACTGAGAT (SEQ ID NO: 2361) hCV596337CAGTGACAAGGGAAGATTGACACAT (SEQ ID NO: 2364) hCV596663GAGGGATAAATACATCAATGGCACAAAGA (SEQ ID NO: 2367) hCV596669GCAGGGATGTCAAGGGACTAGA (SEQ ID NO: 2370) hCV7422466GTTTGGGATGGCACAATGATTTATG (SEQ ID NO: 2373) hCV7429782ATCCTCCAATCTTCCTCCCCATATC (SEQ ID NO: 2376) hCV7429793CTCTGGCTTGAAGGGCAAAGAC (SEQ ID NO: 2379) hCV7459627 TGCCACATGCTTCTTCTAAC(SEQ ID NO: 2382) hCV7504118 AAACAGTTCGAGGATACACACAATCTCA (SEQ ID NO:2385) hCV7574127 GAAACAGTTGGTCAAACTGACAAGA (SEQ ID NO: 2388) hCV7581501TCCATCCACCGCTTACTG (SEQ ID NO: 2391) hCV7584272 TGGCTCAGTTCTTTTTCTTCTAT(SEQ ID NO: 2394) hCV7625318 TCAAGCTGAGGGTGGTCTAG (SEQ ID NO: 2397)hCV788647 TGTCCACTCCTGGCACACTT (SEQ ID NO: 2400) hCV813581GAGCATATTCCCCACCACAGTT (SEQ ID NO: 2403) hCV815038CATTTTGCACCCAACCACAACT (SEQ ID NO: 2406) hCV8241630CCTCTCAAGCAAATACGCCTTGAA (SEQ ID NO: 2409) hCV8361354GCAATGCACGTGACCATCTT (SEQ ID NO: 2412) hCV837462TGGACATATGCTATTGACTTTAAAA (SEQ ID NO: 2415) hCV8598986 GGAGGCCCTGCCAGATG(SEQ ID NO: 2418) hCV8688111 GTCACAGATCATTTATCACAGTGTACCAT (SEQ ID NO:2421) hCV8703249 AAGCTAGAGGATGGTCCCAGTTTTAC (SEQ ID NO: 2424) hCV8717752GGCAGAAGTGACAGTAGGTTAGTCT (SEQ ID NO: 2427) hCV8717873TGTGAAAGAACCAACTGAATTAAA (SEQ ID NO: 2430) hCV8717893CGCTGAACTGACCGTCTCATTC (SEQ ID NO: 2433) hCV8717916 TTGTACCCCAGGTTGAAAAT(SEQ ID NO: 2436) hCV8717949 GGGAACAGGTGTTCACATCA (SEQ ID NO: 2439)hCV8726802 CCAGGTGGTGGATTCTTAAGT (SEQ ID NO: 2442) hCV8727391TTCCTAGGCCCAAACAGA (SEQ ID NO: 2445) hCV8827309AAGTTGGATCGAGTTATAACAACTATA (SEQ ID NO: 2448) hCV8856223CCTGCTTTGCGTCTGAAGAGATAT (SEQ ID NO: 2451) hCV8857351AGCCTGCTGTCCTGCTCTAT (SEQ ID NO: 2454) hCV8911768CTGATTTTGCTCCAATAGGCACTTTT (SEQ ID NO: 2457) hCV8919442GGTGTCTCCCAACTTTATGTG (SEQ ID NO: 2460) hCV8919444 GGTGTCTCCCAACTTTATGTG(SEQ ID NO: 2463) hCV8919450 CAAGGTTATTGACAGTGAACTTACT (SEQ ID NO: 2466)hCV8919451 TTTGAACCTCCAGAATCTACAG (SEQ ID NO: 2469) hCV8941510GGGCTACTTCACCAAAGAGAA (SEQ ID NO: 2472) hCV8957432 CCTGACTGGCAAGGTTTAAA(SEQ ID NO: 2475) hCV9102827 TGCTGACTCCAGCTCTTTC (SEQ ID NO: 2478)hCV9114656 ATATTCGGATCTGTTTTCAACTTA (SEQ ID NO: 2481) hCV916106GTGGTTGTCTGCAGTTTTCAAATGTT (SEQ ID NO: 2484) hCV916107TTCAGCTTTTTATTGAACACATTATA (SEQ ID NO: 2487) hCV926518 CCCAGCTGCCAAATTTC(SEQ ID NO: 2490) hCV9327878 TGACCTGAACGACTTCACAG (SEQ ID NO: 2493)hCV9493081 TTCATCCCTGGCTTCACAGTACAT (SEQ ID NO: 2496) hCV949676CACCCCCACTTGTCAAAT (SEQ ID NO: 2499) hCV9596963 GGCCCTCCAGGATCTG (SEQ IDNO: 2502) hCV9680592 TTTGAACAGGCACTCACTAATAG (SEQ ID NO: 2505) hCV97631GCACACACACGTCATCATATCTTCA (SEQ ID NO: 2508) hCV9860072GCTCTCCCTGTTTCAGACAT (SEQ ID NO: 2511) hDV70662128 GCGGACGGGAAGATGTTGAT(SEQ ID NO: 2514) hDV70683187 CTGTAAGCAGTTTGGGCTCTTTTAAT (SEQ ID NO:2517) hDV70683212 CCAGCCAGGCAAGGTTAAGTC (SEQ ID NO: 2520) hDV70683382CAACTACTCTTAGAATTAAAGGCACAGCT (SEQ ID NO: 2523) hDV70941043AGGAAGAAGGCTCCTGTGTTCTAAT (SEQ ID NO: 2526) hDV70965621GGGAGTGGAACACAGGTGAGA (SEQ ID NO: 2529) hDV71075942 TGCCAGAGGCGCATGTG(SEQ ID NO: 2532) hDV76976792 GGCAGGCATTCTCAAGAATCCT (SEQ ID NO: 2535)hDV76976795 GAACTGAAATCCTCCAAGTCGATCTAG (SEQ ID NO: 2538) hCV1841974CCCTCAGCCAGCCACTATG (SEQ ID NO: 2541) hCV1952126GGTCACTTCTAGTCTGGTATCCATTATCAT (SEQ ID NO: 2544) hCV22272816CGGCGCTGGTGAGAC (SEQ ID NO: 2547) hCV25597241 TCCTGCTTTGCTCTGGTATCA (SEQID NO: 2550) hCV30500334 AGTGTGGAGGGACCCTGATAAC (SEQ ID NO: 2553)hCV30747430 AAGCTTATGGTGGTCCCAGTTAGT (SEQ ID NO: 2556)

TABLE 4 Interrogated SNP Interrogated rs LD SNP LD SNP rs PowerThreshold r² r² hCV11503414 rs2066865 hCV11503416 rs2066864 0.510.528621503 1 hCV11503414 rs2066865 hCV11503431 rs2066861 0.510.528621503 1 hCV11503414 rs2066865 hCV11853483 rs12644950 0.510.528621503 1 hCV11503414 rs2066865 hCV11853489 rs7681423 0.510.528621503 1 hCV11503414 rs2066865 hCV11853496 rs7654093 0.510.528621503 1 hCV11503414 rs2066865 hCV27020277 rs6825454 0.510.528621503 0.9115 hCV11503414 rs2066865 hCV2892859 rs13130318 0.510.528621503 0.8654 hCV11503414 rs2066865 hCV2892869 rs13109457 0.510.528621503 0.9571 hCV11503414 rs2066865 hCV2892877 rs6050 0.510.528621503 0.9148 hCV11503414 rs2066865 hCV31863982 rs7659024 0.510.528621503 1 hCV11503431 rs2066861 hCV11503414 rs2066865 0.510.521395339 1 hCV11503431 rs2066861 hCV11503416 rs2066864 0.510.521395339 1 hCV11503431 rs2066861 hCV11853483 rs12644950 0.510.521395339 1 hCV11503431 rs2066861 hCV11853489 rs7681423 0.510.521395339 1 hCV11503431 rs2066861 hCV11853496 rs7654093 0.510.521395339 1 hCV11503431 rs2066861 hCV15860433 rs2070006 0.510.521395339 0.5225 hCV11503431 rs2066861 hCV27020269 rs7659613 0.510.521395339 0.5225 hCV11503431 rs2066861 hCV27020277 rs6825454 0.510.521395339 0.9115 hCV11503431 rs2066861 hCV2892859 rs13130318 0.510.521395339 0.8654 hCV11503431 rs2066861 hCV2892869 rs13109457 0.510.521395339 0.9571 hCV11503431 rs2066861 hCV2892877 rs6050 0.510.521395339 0.9148 hCV11503431 rs2066861 hCV31863982 rs7659024 0.510.521395339 1 hCV11853483 rs12644950 hCV11503414 rs2066865 0.510.506269027 1 hCV11853483 rs12644950 hCV11503416 rs2066864 0.510.506269027 1 hCV11853483 rs12644950 hCV11503431 rs2066861 0.510.506269027 1 hCV11853483 rs12644950 hCV11853489 rs7681423 0.510.506269027 1 hCV11853483 rs12644950 hCV11853496 rs7654093 0.510.506269027 1 hCV11853483 rs12644950 hCV27020277 rs6825454 0.510.506269027 0.9041 hCV11853483 rs12644950 hCV2892859 rs13130318 0.510.506269027 0.8547 hCV11853483 rs12644950 hCV2892869 rs13109457 0.510.506269027 0.9537 hCV11853483 rs12644950 hCV2892877 rs6050 0.510.506269027 0.9079 hCV11853483 rs12644950 hCV31863982 rs7659024 0.510.506269027 1 hCV11853496 rs7654093 hCV11503414 rs2066865 0.510.521395339 1 hCV11853496 rs7654093 hCV11503416 rs2066864 0.510.521395339 1 hCV11853496 rs7654093 hCV11503431 rs2066861 0.510.521395339 1 hCV11853496 rs7654093 hCV11853483 rs12644950 0.510.521395339 1 hCV11853496 rs7654093 hCV11853489 rs7681423 0.510.521395339 1 hCV11853496 rs7654093 hCV27020277 rs6825454 0.510.521395339 0.9109 hCV11853496 rs7654093 hCV2892859 rs13130318 0.510.521395339 0.8643 hCV11853496 rs7654093 hCV2892869 rs13109457 0.510.521395339 0.9568 hCV11853496 rs7654093 hCV2892877 rs6050 0.510.521395339 0.9143 hCV11853496 rs7654093 hCV31863982 rs7659024 0.510.521395339 1 hCV1198623 rs2638504 hCV16269565 rs2682338 0.510.946056388 0.9622 hCV1198623 rs2638504 hCV444705 rs6580917 0.510.946056388 0.9614 hCV12066124 rs2036914 hCV2103343 rs4241824 0.510.734459115 0.9351 hCV12066124 rs2036914 hCV25474413 rs3822057 0.510.734459115 0.9351 hCV15860433 rs2070006 hCV27020269 rs7659613 0.510.884364576 1 hCV15860433 rs2070006 hCV2892870 rs2070011 0.510.884364576 0.9647 hCV15885425 rs2290754 hCV15760229 rs3006939 0.510.641487193 0.6943 hCV15885425 rs2290754 hCV15760238 rs3006936 0.510.641487193 0.7059 hCV15885425 rs2290754 hCV15823024 rs2125230 0.510.641487193 1 hCV15885425 rs2290754 hCV15965338 rs2291410 0.510.641487193 1 hCV15885425 rs2290754 hCV16082410 rs2881275 0.510.641487193 1 hCV15885425 rs2290754 hCV1678656 rs1458024 0.510.641487193 1 hCV15885425 rs2290754 hCV1678674 rs1458023 0.510.641487193 0.8095 hCV15885425 rs2290754 hCV1678682 rs320339 0.510.641487193 0.8718 hCV15885425 rs2290754 hCV26034158 rs4515770 0.510.641487193 0.6976 hCV15885425 rs2290754 hCV26719082 rs10927046 0.510.641487193 0.8715 hCV15885425 rs2290754 hCV26719085 rs10927047 0.510.641487193 0.8649 hCV15885425 rs2290754 hCV26719107 rs7538011 0.510.641487193 0.81 hCV15885425 rs2290754 hCV26719113 rs7517340 0.510.641487193 0.9318 hCV15885425 rs2290754 hCV26719116 rs10927039 0.510.641487193 0.8711 hCV15885425 rs2290754 hCV26719120 rs10927040 0.510.641487193 1 hCV15885425 rs2290754 hCV26719121 rs10927041 0.510.641487193 0.8181 hCV15885425 rs2290754 hCV26719149 rs6675851 0.510.641487193 1 hCV15885425 rs2290754 hCV26719162 rs4132509 0.510.641487193 1 hCV15885425 rs2290754 hCV26719176 rs10927076 0.510.641487193 1 hCV15885425 rs2290754 hCV26719192 rs10803161 0.510.641487193 1 hCV15885425 rs2290754 hCV26719201 rs4478795 0.510.641487193 0.7462 hCV15885425 rs2290754 hCV26719219 rs9782958 0.510.641487193 1 hCV15885425 rs2290754 hCV26719222 rs4553169 0.510.641487193 1 hCV15885425 rs2290754 hCV26719227 rs10927065 0.510.641487193 0.8095 hCV15885425 rs2290754 hCV26719232 rs10803158 0.510.641487193 1 hCV15885425 rs2290754 hCV26719233 rs10927067 0.510.641487193 1 hCV15885425 rs2290754 hCV27498250 rs3766673 0.510.641487193 0.8792 hCV15885425 rs2290754 hCV29210363 rs6656918 0.510.641487193 0.6952 hCV15885425 rs2290754 hCV29542869 rs7534117 0.510.641487193 1 hCV15885425 rs2290754 hCV29560960 rs7519673 0.510.641487193 0.8095 hCV15885425 rs2290754 hCV29741723 rs7517921 0.510.641487193 0.7042 hCV15885425 rs2290754 hCV29994467 rs6694738 0.510.641487193 0.81 hCV15885425 rs2290754 hCV30084348 rs9287269 0.510.641487193 1 hCV15885425 rs2290754 hCV30372886 rs9782883 0.510.641487193 1 hCV15885425 rs2290754 hCV30690780 rs10737888 0.510.641487193 0.7059 hCV15885425 rs2290754 hCV31523557 rs10754807 0.510.641487193 1 hCV15885425 rs2290754 hCV31523563 rs10927051 0.510.641487193 0.923 hCV15885425 rs2290754 hCV31523638 rs12037013 0.510.641487193 0.8715 hCV15885425 rs2290754 hCV31523639 rs12034588 0.510.641487193 1 hCV15885425 rs2290754 hCV31523643 rs6671475 0.510.641487193 0.9347 hCV15885425 rs2290754 hCV31523650 rs12048930 0.510.641487193 0.8181 hCV15885425 rs2290754 hCV31523658 rs12047209 0.510.641487193 0.7481 hCV15885425 rs2290754 hCV31523688 rs12049228 0.510.641487193 1 hCV15885425 rs2290754 hCV31523691 rs12021907 0.510.641487193 0.8095 hCV15885425 rs2290754 hCV31523707 rs10803152 0.510.641487193 0.8652 hCV15885425 rs2290754 hCV31523710 rs10927059 0.510.641487193 1 hCV15885425 rs2290754 hCV31523723 rs12140040 0.510.641487193 0.7484 hCV15885425 rs2290754 hCV31523736 rs12124113 0.510.641487193 0.8091 hCV15885425 rs2290754 hCV31523740 rs12032342 0.510.641487193 1 hCV15885425 rs2290754 hCV31523744 rs12031994 0.510.641487193 0.8095 hCV15885425 rs2290754 hCV804126 rs320320 0.510.641487193 1 hCV15885425 rs2290754 hCV97631 rs1538773 0.51 0.6414871930.7059 hCV15885425 rs2290754 hDV71836703 rs6429433 0.51 0.641487193 0.81hCV16000557 rs2377041 hCV1642008 rs1563471 0.51 0.48606158 0.8362hCV16000557 rs2377041 hCV1974943 rs6672381 0.51 0.48606158 0.4957hCV16000557 rs2377041 hCV1974944 rs6667605 0.51 0.48606158 0.4885hCV16000557 rs2377041 hCV27102953 rs4648360 0.51 0.48606158 0.8987hCV16000557 rs2377041 hCV27102978 rs7537581 0.51 0.48606158 0.8288hCV16000557 rs2377041 hCV27103080 rs4648459 0.51 0.48606158 1hCV16000557 rs2377041 hCV27103144 rs11584658 0.51 0.48606158 0.8636hCV16000557 rs2377041 hCV27103182 rs4609377 0.51 0.48606158 0.7742hCV16000557 rs2377041 hCV27103185 rs10797389 0.51 0.48606158 0.8506hCV16000557 rs2377041 hCV27103186 rs4648481 0.51 0.48606158 0.8659hCV16000557 rs2377041 hCV27103188 rs7511879 0.51 0.48606158 0.7719hCV16000557 rs2377041 hCV27103189 rs12031493 0.51 0.48606158 0.738hCV16000557 rs2377041 hCV27103192 rs6680471 0.51 0.48606158 0.6533hCV16000557 rs2377041 hCV27103207 rs6424062 0.51 0.48606158 1hCV16000557 rs2377041 hCV31475436 rs4486391 0.51 0.48606158 0.503hCV16000557 rs2377041 hCV31965210 rs10909880 0.51 0.48606158 0.8659hCV16000557 rs2377041 hCV31965333 rs10797390 0.51 0.48606158 0.7352hCV16000557 rs2377041 hCV788647 rs729045 0.51 0.48606158 0.5863hCV16000557 rs2377041 hCV8725828 rs1456461 0.51 0.48606158 0.5812hCV1678674 rs1458023 hCV15823024 rs2125230 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV15885425 rs2290754 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV15965338 rs2291410 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV16082410 rs2881275 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV1678656 rs1458024 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV1678682 rs320339 0.51 0.6955117 0.7908hCV1678674 rs1458023 hCV26719082 rs10927046 0.51 0.6955117 0.9284hCV1678674 rs1458023 hCV26719085 rs10927047 0.51 0.6955117 0.9242hCV1678674 rs1458023 hCV26719107 rs7538011 0.51 0.6955117 0.8655hCV1678674 rs1458023 hCV26719113 rs7517340 0.51 0.6955117 0.721hCV1678674 rs1458023 hCV26719116 rs10927039 0.51 0.6955117 0.7473hCV1678674 rs1458023 hCV26719120 rs10927040 0.51 0.6955117 0.7884hCV1678674 rs1458023 hCV26719149 rs6675851 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV26719162 rs4132509 0.51 0.6955117 0.8095hCV1678674 rs1458023 hCV26719176 rs10927076 0.51 0.6955117 0.776hCV1678674 rs1458023 hCV26719192 rs10803161 0.51 0.6955117 0.7993hCV1678674 rs1458023 hCV26719201 rs4478795 0.51 0.6955117 0.9 hCV1678674rs1458023 hCV26719219 rs9782958 0.51 0.6955117 0.8095 hCV1678674rs1458023 hCV26719222 rs4553169 0.51 0.6955117 0.8086 hCV1678674rs1458023 hCV26719227 rs10927065 0.51 0.6955117 1 hCV1678674 rs1458023hCV26719232 rs10803158 0.51 0.6955117 0.8095 hCV1678674 rs1458023hCV26719233 rs10927067 0.51 0.6955117 0.8095 hCV1678674 rs1458023hCV29542869 rs7534117 0.51 0.6955117 0.8095 hCV1678674 rs1458023hCV29560960 rs7519673 0.51 0.6955117 1 hCV1678674 rs1458023 hCV29994467rs6694738 0.51 0.6955117 0.8655 hCV1678674 rs1458023 hCV30084348rs9287269 0.51 0.6955117 0.8095 hCV1678674 rs1458023 hCV30372886rs9782883 0.51 0.6955117 0.8095 hCV1678674 rs1458023 hCV31523557rs10754807 0.51 0.6955117 0.8091 hCV1678674 rs1458023 hCV31523638rs12037013 0.51 0.6955117 0.9284 hCV1678674 rs1458023 hCV31523639rs12034588 0.51 0.6955117 0.7993 hCV1678674 rs1458023 hCV31523643rs6671475 0.51 0.6955117 0.7467 hCV1678674 rs1458023 hCV31523658rs12047209 0.51 0.6955117 0.9286 hCV1678674 rs1458023 hCV31523688rs12049228 0.51 0.6955117 0.7998 hCV1678674 rs1458023 hCV31523691rs12021907 0.51 0.6955117 1 hCV1678674 rs1458023 hCV31523707 rs108031520.51 0.6955117 0.9244 hCV1678674 rs1458023 hCV31523710 rs10927059 0.510.6955117 0.8095 hCV1678674 rs1458023 hCV31523723 rs12140040 0.510.6955117 0.9245 hCV1678674 rs1458023 hCV31523736 rs12124113 0.510.6955117 1 hCV1678674 rs1458023 hCV31523740 rs12032342 0.51 0.69551170.8095 hCV1678674 rs1458023 hCV31523744 rs12031994 0.51 0.6955117 1hCV1678674 rs1458023 hCV804126 rs320320 0.51 0.6955117 0.8095 hCV1678674rs1458023 hDV71836703 rs6429433 0.51 0.6955117 0.7358 hCV1678682rs320339 hCV15823024 rs2125230 0.51 0.68963884 0.8718 hCV1678682rs320339 hCV15885425 rs2290754 0.51 0.68963884 0.8718 hCV1678682rs320339 hCV15965338 rs2291410 0.51 0.68963884 0.8718 hCV1678682rs320339 hCV16082410 rs2881275 0.51 0.68963884 0.8718 hCV1678682rs320339 hCV1678656 rs1458024 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV1678674 rs1458023 0.51 0.68963884 0.7908 hCV1678682 rs320339hCV26719082 rs10927046 0.51 0.68963884 0.8604 hCV1678682 rs320339hCV26719085 rs10927047 0.51 0.68963884 0.8524 hCV1678682 rs320339hCV26719107 rs7538011 0.51 0.68963884 0.801 hCV1678682 rs320339hCV26719113 rs7517340 0.51 0.68963884 0.7898 hCV1678682 rs320339hCV26719116 rs10927039 0.51 0.68963884 0.8086 hCV1678682 rs320339hCV26719120 rs10927040 0.51 0.68963884 0.8575 hCV1678682 rs320339hCV26719121 rs10927041 0.51 0.68963884 0.7003 hCV1678682 rs320339hCV26719149 rs6675851 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV26719162 rs4132509 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV26719176 rs10927076 0.51 0.68963884 0.8492 hCV1678682 rs320339hCV26719192 rs10803161 0.51 0.68963884 0.8649 hCV1678682 rs320339hCV26719201 rs4478795 0.51 0.68963884 0.7099 hCV1678682 rs320339hCV26719219 rs9782958 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV26719222 rs4553169 0.51 0.68963884 0.8711 hCV1678682 rs320339hCV26719227 rs10927065 0.51 0.68963884 0.7908 hCV1678682 rs320339hCV26719232 rs10803158 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV26719233 rs10927067 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV27498250 rs3766673 0.51 0.68963884 0.7611 hCV1678682 rs320339hCV29542869 rs7534117 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV29560960 rs7519673 0.51 0.68963884 0.7908 hCV1678682 rs320339hCV29994467 rs6694738 0.51 0.68963884 0.801 hCV1678682 rs320339hCV30084348 rs9287269 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV30372886 rs9782883 0.51 0.68963884 0.8718 hCV1678682 rs320339hCV31523557 rs10754807 0.51 0.68963884 0.8715 hCV1678682 rs320339hCV31523563 rs10927051 0.51 0.68963884 0.7601 hCV1678682 rs320339hCV31523638 rs12037013 0.51 0.68963884 0.8604 hCV1678682 rs320339hCV31523639 rs12034588 0.51 0.68963884 0.8649 hCV1678682 rs320339hCV31523643 rs6671475 0.51 0.68963884 0.8081 hCV1678682 rs320339hCV31523650 rs12048930 0.51 0.68963884 0.7003 hCV1678682 rs320339hCV31523658 rs12047209 0.51 0.68963884 0.732 hCV1678682 rs320339hCV31523688 rs12049228 0.51 0.68963884 0.8652 hCV1678682 rs320339hCV31523691 rs12021907 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hCV2288095 rs378815hCV26016183 rs9887617 0.51 0.721860657 0.9162 hCV2288095 rs378815hCV27904396 rs4829996 0.51 0.721860657 0.9459 hCV2288095 rs378815hCV28962605 rs5930005 0.51 0.721860657 0.9576 hCV2288095 rs378815hCV29515877 rs5930015 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV29732937 rs5931647 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV29967889 rs5931645 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV30130033 rs5931646 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV30201992 rs5931641 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV30291634 rs5931666 0.51 0.721860657 0.9562 hCV2288095 rs378815hCV30700232 rs12687091 0.51 0.721860657 0.9579 hCV2288095 rs378815hCV596663 rs411017 0.51 0.721860657 1 hCV2288095 rs378815 hCV596665rs401597 0.51 0.721860657 0.9459 hCV2288095 rs378815 hDV77022847rs4598407 0.51 0.721860657 0.9579 hCV2288095 rs378815 hDV77148131rs5931661 0.51 0.721860657 0.9116 hCV2288095 rs378815 hDV77150953rs5976389 0.51 0.721860657 0.9579 hCV233148 rs1417121 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hCV233148 rs1417121 hCV97631 rs1538773 0.51 0.506335570.6656 hCV2456747 rs3820059 hCV11341869 rs2176473 0.51 0.699341435 0.873hCV2456747 rs3820059 hCV11341876 rs1980198 0.51 0.699341435 0.8561hCV2456747 rs3820059 hCV11341878 rs4656670 0.51 0.699341435 0.873hCV2456747 rs3820059 hCV11341882 rs12024897 0.51 0.699341435 0.873hCV2456747 rs3820059 hCV11341886 rs7539415 0.51 0.699341435 0.873hCV2456747 rs3820059 hCV11341887 rs3766095 0.51 0.699341435 1 hCV2456747rs3820059 hCV11341898 rs12563090 0.51 0.699341435 0.8681 hCV2456747rs3820059 hCV11975148 rs2037250 0.51 0.699341435 0.7895 hCV2456747rs3820059 hCV11975152 rs1856303 0.51 0.699341435 0.7895 hCV2456747rs3820059 hCV15878582 rs2275299 0.51 0.699341435 0.8709 hCV2456747rs3820059 hCV221700 rs6677410 0.51 0.699341435 0.8709 hCV2456747rs3820059 hCV2456730 rs961404 0.51 0.699341435 0.873 hCV2456747rs3820059 hCV2456741 rs6696810 0.51 0.699341435 0.873 hCV2456747rs3820059 hCV2456753 rs7528375 0.51 0.699341435 0.8688 hCV2456747rs3820059 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hCV31523643 rs6671475 hCV29560960 rs7519673 0.510.736259252 0.7467 hCV31523643 rs6671475 hCV29741723 rs7517921 0.510.736259252 0.7503 hCV31523643 rs6671475 hCV29994467 rs6694738 0.510.736259252 0.8707 hCV31523643 rs6671475 hCV30084348 rs9287269 0.510.736259252 0.9347 hCV31523643 rs6671475 hCV30372886 rs9782883 0.510.736259252 0.9347 hCV31523643 rs6671475 hCV30690780 rs10737888 0.510.736259252 0.7841 hCV31523643 rs6671475 hCV31523557 rs10754807 0.510.736259252 0.9345 hCV31523643 rs6671475 hCV31523563 rs10927051 0.510.736259252 0.8551 hCV31523643 rs6671475 hCV31523638 rs12037013 0.510.736259252 0.8076 hCV31523643 rs6671475 hCV31523639 rs12034588 0.510.736259252 0.9312 hCV31523643 rs6671475 hCV31523650 rs12048930 0.510.736259252 0.752 hCV31523643 rs6671475 hCV31523688 rs12049228 0.510.736259252 0.9314 hCV31523643 rs6671475 hCV31523691 rs12021907 0.510.736259252 0.7467 hCV31523643 rs6671475 hCV31523707 rs10803152 0.510.736259252 0.7983 hCV31523643 rs6671475 hCV31523710 rs10927059 0.510.736259252 0.9347 hCV31523643 rs6671475 hCV31523736 rs12124113 0.510.736259252 0.746 hCV31523643 rs6671475 hCV31523740 rs12032342 0.510.736259252 0.9347 hCV31523643 rs6671475 hCV31523744 rs12031994 0.510.736259252 0.7467 hCV31523643 rs6671475 hCV804126 rs320320 0.510.736259252 0.9347 hCV31523643 rs6671475 hCV97631 rs1538773 0.510.736259252 0.7841 hCV31523643 rs6671475 hDV71836703 rs6429433 0.510.736259252 0.8707 hCV31523650 rs12048930 hCV26719120 rs10927040 0.510.888920337 0.9316 hCV31523650 rs12048930 hCV31523563 rs10927051 0.510.888920337 0.923 hCV31523650 rs12048930 hCV31523639 rs12034588 0.510.888920337 0.9349 hCV31863982 rs7659024 hCV11503414 rs2066865 0.510.477476354 1 hCV31863982 rs7659024 hCV11503416 rs2066864 0.510.477476354 1 hCV31863982 rs7659024 hCV11503431 rs2066861 0.510.477476354 1 hCV31863982 rs7659024 hCV11853483 rs12644950 0.510.477476354 1 hCV31863982 rs7659024 hCV11853489 rs7681423 0.510.477476354 1 hCV31863982 rs7659024 hCV11853496 rs7654093 0.510.477476354 1 hCV31863982 rs7659024 hCV15860433 rs2070006 0.510.477476354 0.5225 hCV31863982 rs7659024 hCV27020269 rs7659613 0.510.477476354 0.5225 hCV31863982 rs7659024 hCV27020277 rs6825454 0.510.477476354 0.9115 hCV31863982 rs7659024 hCV2892859 rs13130318 0.510.477476354 0.8654 hCV31863982 rs7659024 hCV2892869 rs13109457 0.510.477476354 0.9571 hCV31863982 rs7659024 hCV2892877 rs6050 0.510.477476354 0.9148 hCV31965333 rs10797390 hCV16000557 rs2377041 0.510.676094947 0.7352 hCV31965333 rs10797390 hCV1642008 rs1563471 0.510.676094947 0.7255 hCV31965333 rs10797390 hCV27102953 rs4648360 0.510.676094947 0.7827 hCV31965333 rs10797390 hCV27102978 rs7537581 0.510.676094947 0.7038 hCV31965333 rs10797390 hCV27103080 rs4648459 0.510.676094947 0.7405 hCV31965333 rs10797390 hCV27103144 rs11584658 0.510.676094947 0.8469 hCV31965333 rs10797390 hCV27103182 rs4609377 0.510.676094947 0.7768 hCV31965333 rs10797390 hCV27103185 rs10797389 0.510.676094947 0.8326 hCV31965333 rs10797390 hCV27103186 rs4648481 0.510.676094947 0.8158 hCV31965333 rs10797390 hCV27103188 rs7511879 0.510.676094947 0.7786 hCV31965333 rs10797390 hCV27103189 rs12031493 0.510.676094947 0.8473 hCV31965333 rs10797390 hCV27103192 rs6680471 0.510.676094947 0.8159 hCV31965333 rs10797390 hCV27103207 rs6424062 0.510.676094947 0.7449 hCV31965333 rs10797390 hCV31965210 rs10909880 0.510.676094947 0.8158 hCV31965333 rs10797390 hCV788647 rs729045 0.510.676094947 0.9244 hCV3216426 rs7315731 hCV1026394 rs35117 0.510.727697779 0.9666 hCV3216426 rs7315731 hCV1026396 rs35115 0.510.727697779 0.9344 hCV3216426 rs7315731 hCV1026401 rs35122 0.510.727697779 0.9318 hCV3216426 rs7315731 hCV1026402 rs247929 0.510.727697779 0.9652 hCV3216426 rs7315731 hCV1026405 rs997307 0.510.727697779 1 hCV3216426 rs7315731 hCV12058175 rs10880879 0.510.727697779 1 hCV3216426 rs7315731 hCV2071465 rs10880884 0.510.727697779 0.9664 hCV3216426 rs7315731 hCV2362878 rs247918 0.510.727697779 0.888 hCV3216426 rs7315731 hCV26024786 rs7976870 0.510.727697779 0.9652 hCV3216426 rs7315731 hCV26173954 rs7308284 0.510.727697779 0.7488 hCV3216426 rs7315731 hCV26173968 rs10880880 0.510.727697779 1 hCV3216426 rs7315731 hCV26173972 rs1012642 0.510.727697779 1 hCV3216426 rs7315731 hCV2773478 rs2193749 0.51 0.7276977790.9666 hCV3216426 rs7315731 hCV2773479 rs7138997 0.51 0.727697779 0.9344hCV3216426 rs7315731 hCV2791821 rs2059404 0.51 0.727697779 0.8909hCV3216426 rs7315731 hCV2791832 rs2408435 0.51 0.727697779 0.9641hCV3216426 rs7315731 hCV2791836 rs7132422 0.51 0.727697779 0.966hCV3216426 rs7315731 hCV30311491 rs6582585 0.51 0.727697779 0.7488hCV3216426 rs7315731 hCV30680015 rs6582574 0.51 0.727697779 0.9658hCV3216426 rs7315731 hCV30870058 rs11183272 0.51 0.727697779 1hCV3216426 rs7315731 hCV30870104 rs10880875 0.51 0.727697779 1hCV3216426 rs7315731 hCV30870137 rs10880871 0.51 0.727697779 1hCV3216426 rs7315731 hCV31416750 rs10880855 0.51 0.727697779 0.9666hCV3216426 rs7315731 hCV31416763 rs12319077 0.51 0.727697779 0.9329hCV3216426 rs7315731 hCV31416770 rs11183201 0.51 0.727697779 0.9661hCV3216426 rs7315731 hCV3201166 rs11183243 0.51 0.727697779 1 hCV3216426rs7315731 hCV3216410 rs247930 0.51 0.727697779 0.9666 hCV3216426rs7315731 hCV3216415 rs247920 0.51 0.727697779 0.9344 hCV3216426rs7315731 hCV3216418 rs35125 0.51 0.727697779 0.9666 hCV3216426rs7315731 hCV3216425 rs1366024 0.51 0.727697779 0.9666 hCV3216426rs7315731 hCV3216427 rs724909 0.51 0.727697779 1 hCV3216426 rs7315731hCV3216433 rs7306229 0.51 0.727697779 1 hCV3216426 rs7315731 hCV345121rs10748432 0.51 0.727697779 0.9578 hCV3216426 rs7315731 hCV389695rs2408461 0.51 0.727697779 0.7488 hCV491830 rs3087546 hCV11280343rs12222447 0.51 0.804397523 0.8924 hCV596326 rs398101 hCV596330 rs4221870.51 0.794342915 0.8217 hCV596326 rs398101 hCV596331 rs6048 0.510.794342915 0.8216 hCV596331 rs6048 hCV596330 rs422187 0.51 0.9594561951 hCV596663 rs411017 hCV11780206 rs5931656 0.51 0.674917535 0.9579hCV596663 rs411017 hCV11780209 rs5930009 0.51 0.674917535 0.9579hCV596663 rs411017 hCV11780214 rs7878061 0.51 0.674917535 0.9579hCV596663 rs411017 hCV2288095 rs378815 0.51 0.674917535 1 hCV596663rs411017 hCV26011954 rs4620439 0.51 0.674917535 0.9579 hCV596663rs411017 hCV26011955 rs5930013 0.51 0.674917535 0.9579 hCV596663rs411017 hCV26016182 rs11796672 0.51 0.674917535 0.9579 hCV596663rs411017 hCV26016183 rs9887617 0.51 0.674917535 0.9162 hCV596663rs411017 hCV27904396 rs4829996 0.51 0.674917535 0.9459 hCV596663rs411017 hCV28962605 rs5930005 0.51 0.674917535 0.9576 hCV596663rs411017 hCV29515877 rs5930015 0.51 0.674917535 0.9579 hCV596663rs411017 hCV29732937 rs5931647 0.51 0.674917535 0.9579 hCV596663rs411017 hCV29967889 rs5931645 0.51 0.674917535 0.9579 hCV596663rs411017 hCV30130033 rs5931646 0.51 0.674917535 0.9579 hCV596663rs411017 hCV30201992 rs5931641 0.51 0.674917535 0.9579 hCV596663rs411017 hCV30291634 rs5931666 0.51 0.674917535 0.9562 hCV596663rs411017 hCV30700232 rs12687091 0.51 0.674917535 0.9579 hCV596663rs411017 hCV596665 rs401597 0.51 0.674917535 0.9459 hCV596663 rs411017hDV77022847 rs4598407 0.51 0.674917535 0.9579 hCV596663 rs411017hDV77148131 rs5931661 0.51 0.674917535 0.9116 hCV596663 rs411017hDV77150953 rs5976389 0.51 0.674917535 0.9579 hCV788647 rs729045hCV31965333 rs10797390 0.51 0.862222906 0.9244 hCV8361354 rs1138800hCV16176508 rs2949857 0.51 0.697573042 0.7785 hCV8361354 rs1138800hCV16176534 rs2949863 0.51 0.697573042 0.7785 hCV8361354 rs1138800hCV204260 rs4753535 0.51 0.697573042 0.743 hCV8361354 rs1138800hCV260722 rs4073615 0.51 0.697573042 0.8988 hCV8361354 rs1138800hCV26487026 rs4753543 0.51 0.697573042 0.808 hCV8361354 rs1138800hCV29137668 rs7108501 0.51 0.697573042 0.7385 hCV8361354 rs1138800hCV29137679 rs6483293 0.51 0.697573042 0.8651 hCV8361354 rs1138800hCV31252427 rs4625415 0.51 0.697573042 0.7785 hCV8361354 rs1138800hCV31252429 rs12222234 0.51 0.697573042 0.755 hCV8361354 rs1138800hCV389113 rs7927016 0.51 0.697573042 0.7785 hCV8361354 rs1138800hCV389115 rs4531426 0.51 0.697573042 0.7785 hCV8361354 rs1138800hCV389118 rs10437575 0.51 0.697573042 0.7385 hCV8361354 rs1138800hCV389119 rs7925817 0.51 0.697573042 0.738 hCV8361354 rs1138800 hCV89001rs2949858 0.51 0.697573042 0.75 hCV8598986 rs4832233 hCV2105930rs2083168 0.51 0.996752219 1 hCV8598986 rs4832233 hCV2105934 rs20996160.51 0.996752219 1 hCV8598986 rs4832233 hCV2105935 rs3937593 0.510.996752219 1 hCV8598986 rs4832233 hCV2105948 rs6547655 0.51 0.9967522191 hCV8598986 rs4832233 hCV29665700 rs10173155 0.51 0.996752219 1hCV8598986 rs4832233 hCV31173526 rs6547654 0.51 0.996752219 1 hCV8688111rs1578275 hCV30690778 rs12140414 0.51 0.973078677 1 hCV9102827 rs3795733hCV31431621 rs11576266 0.51 0.983113922 1 hCV9493081 rs1058304hCV12073840 rs14403 0.51 0.513841921 0.871 hCV9493081 rs1058304hCV15760229 rs3006939 0.51 0.513841921 0.6575 hCV9493081 rs1058304hCV15760238 rs3006936 0.51 0.513841921 0.6684 hCV9493081 rs1058304hCV15760239 rs3006923 0.51 0.513841921 0.718 hCV9493081 rs1058304hCV233148 rs1417121 0.51 0.513841921 1 hCV9493081 rs1058304 hCV26034157rs2994329 0.51 0.513841921 0.5193 hCV9493081 rs1058304 hCV26034158rs4515770 0.51 0.513841921 0.7088 hCV9493081 rs1058304 hCV26034160rs2994327 0.51 0.513841921 0.7471 hCV9493081 rs1058304 hCV26719121rs10927041 0.51 0.513841921 0.5644 hCV9493081 rs1058304 hCV29210363rs6656918 0.51 0.513841921 0.6589 hCV9493081 rs1058304 hCV30690778rs12140414 0.51 0.513841921 0.5936 hCV9493081 rs1058304 hCV30690780rs10737888 0.51 0.513841921 0.6684 hCV9493081 rs1058304 hCV30690784rs4658574 0.51 0.513841921 0.7471 hCV9493081 rs1058304 hCV8688079rs884808 0.51 0.513841921 0.7471 hCV9493081 rs1058304 hCV8688080rs884328 0.51 0.513841921 0.7459 hCV9493081 rs1058304 hCV8688111rs1578275 0.51 0.513841921 0.5936 hCV9493081 rs1058304 hCV97631rs1538773 0.51 0.513841921 0.6684 hCV97631 rs1538773 hCV12073840 rs144030.51 0.521807277 0.5283 hCV97631 rs1538773 hCV15760229 rs3006939 0.510.521807277 1 hCV97631 rs1538773 hCV15760238 rs3006936 0.51 0.5218072771 hCV97631 rs1538773 hCV15823024 rs2125230 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV15885425 rs2290754 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV15965338 rs2291410 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV16082410 rs2881275 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV1678656 rs1458024 0.51 0.521807277 0.7059 hCV97631rs1538773 hCV1678674 rs1458023 0.51 0.521807277 0.5714 hCV97631rs1538773 hCV1678682 rs320339 0.51 0.521807277 0.6154 hCV97631 rs1538773hCV233148 rs1417121 0.51 0.521807277 0.6656 hCV97631 rs1538773hCV26034158 rs4515770 0.51 0.521807277 1 hCV97631 rs1538773 hCV26719082rs10927046 0.51 0.521807277 0.6144 hCV97631 rs1538773 hCV26719085rs10927047 0.51 0.521807277 0.6005 hCV97631 rs1538773 hCV26719107rs7538011 0.51 0.521807277 0.6602 hCV97631 rs1538773 hCV26719113rs7517340 0.51 0.521807277 0.647 hCV97631 rs1538773 hCV26719116rs10927039 0.51 0.521807277 0.7848 hCV97631 rs1538773 hCV26719120rs10927040 0.51 0.521807277 0.7673 hCV97631 rs1538773 hCV26719121rs10927041 0.51 0.521807277 0.7525 hCV97631 rs1538773 hCV26719149rs6675851 0.51 0.521807277 0.7059 hCV97631 rs1538773 hCV26719162rs4132509 0.51 0.521807277 0.7059 hCV97631 rs1538773 hCV26719176rs10927076 0.51 0.521807277 0.6701 hCV97631 rs1538773 hCV26719192rs10803161 0.51 0.521807277 0.7337 hCV97631 rs1538773 hCV26719219rs9782958 0.51 0.521807277 0.7059 hCV97631 rs1538773 hCV26719222rs4553169 0.51 0.521807277 0.7041 hCV97631 rs1538773 hCV26719227rs10927065 0.51 0.521807277 0.5714 hCV97631 rs1538773 hCV26719232rs10803158 0.51 0.521807277 0.7059 hCV97631 rs1538773 hCV26719233rs10927067 0.51 0.521807277 0.7059 hCV97631 rs1538773 hCV27498250rs3766673 0.51 0.521807277 0.6075 hCV97631 rs1538773 hCV29210363rs6656918 0.51 0.521807277 1 hCV97631 rs1538773 hCV29542869 rs75341170.51 0.521807277 0.7059 hCV97631 rs1538773 hCV29560960 rs7519673 0.510.521807277 0.5714 hCV97631 rs1538773 hCV29741723 rs7517921 0.510.521807277 0.5624 hCV97631 rs1538773 hCV29994467 rs6694738 0.510.521807277 0.6602 hCV97631 rs1538773 hCV30084348 rs9287269 0.510.521807277 0.7059 hCV97631 rs1538773 hCV30372886 rs9782883 0.510.521807277 0.7059 hCV97631 rs1538773 hCV30690778 rs12140414 0.510.521807277 0.898 hCV97631 rs1538773 hCV30690780 rs10737888 0.510.521807277 1 hCV97631 rs1538773 hCV31523557 rs10754807 0.51 0.5218072770.705 hCV97631 rs1538773 hCV31523563 rs10927051 0.51 0.521807277 0.6533hCV97631 rs1538773 hCV31523638 rs12037013 0.51 0.521807277 0.6144hCV97631 rs1538773 hCV31523639 rs12034588 0.51 0.521807277 0.6943hCV97631 rs1538773 hCV31523643 rs6671475 0.51 0.521807277 0.7841hCV97631 rs1538773 hCV31523650 rs12048930 0.51 0.521807277 0.566hCV97631 rs1538773 hCV31523658 rs12047209 0.51 0.521807277 0.5224hCV97631 rs1538773 hCV31523688 rs12049228 0.51 0.521807277 0.6952hCV97631 rs1538773 hCV31523691 rs12021907 0.51 0.521807277 0.5714hCV97631 rs1538773 hCV31523707 rs10803152 0.51 0.521807277 0.6015hCV97631 rs1538773 hCV31523710 rs10927059 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV31523723 rs12140040 0.51 0.521807277 0.5283hCV97631 rs1538773 hCV31523736 rs12124113 0.51 0.521807277 0.5704hCV97631 rs1538773 hCV31523740 rs12032342 0.51 0.521807277 0.7059hCV97631 rs1538773 hCV31523744 rs12031994 0.51 0.521807277 0.5714hCV97631 rs1538773 hCV804126 rs320320 0.51 0.521807277 0.7059 hCV97631rs1538773 hCV8688111 rs1578275 0.51 0.521807277 0.898 hCV97631 rs1538773hCV9493081 rs1058304 0.51 0.521807277 0.6684 hCV97631 rs1538773hDV71836703 rs6429433 0.51 0.521807277 0.6602

TABLE 20 Unadjusted additive and genotypic association of 149 SNPs withDVT in LETS (p <= 0.1) and MEGA-1 (p <= 0.05) P Odds Risk marker annotEndpoint Model parameter Value Ratio OR95l OR95u Allele hCV505733(rs11126416) LETS Gen AA_vs_GG 0.062 1.48 0.98 2.24 A MEGA1 Gen AA_vs_GG0.006 1.36 1.09 1.69 A LETS Gen AA_vs_GG 0.062 1.48 0.98 2.24 A GenAG_vs_GG 0.546 1.09 0.82 1.45 A MEGA1 Gen AA_vs_GG 0.006 1.36 1.09 1.69A Gen AG_vs_GG 0.232 1.1 0.94 1.28 A hCV2879752 (rs1244565) LETS addG_vs_A 0.028 1.23 1.02 1.48 G MEGA1 add G_vs_A 0.036 1.11 1.01 1.23 GLETS Gen GA_vs_AA 0.024 1.45 1.05 1.99 G Gen GG_vs_AA 0.03 1.51 1.042.19 G MEGA1 Gen GA_vs_AA 0.578 1.05 0.89 1.24 G Gen GG_vs_AA 0.032 1.241.02 1.52 G hCV11503470 (rs1800788) MEGA1 add T_vs_C 0.007 1.17 1.041.32 T LETS add T_vs_C 0.014 1.32 1.06 1.65 T LETS Gen TC_vs_CC 0.1481.23 0.93 1.63 T Gen TT_vs_CC 0.02 2.07 1.12 3.83 T MEGA1 Gen TC_vs_CC4E−04 1.31 1.13 1.53 T Gen TT_vs_CC 0.505 1.11 0.82 1.49 T hCV15860433(rs2070006) MEGA1 add T_vs_C 2E−05 1.24 1.13 1.37 T LETS add T_vs_C0.024 1.24 1.03 1.5 T LETS Gen TC_vs_CC 0.328 1.16 0.86 1.56 T GenTT_vs_CC 0.02 1.57 1.07 2.31 T MEGA1 Gen TC_vs_CC 0.003 1.28 1.09 1.5 TGen TT_vs_CC 4E−05 1.54 1.25 1.88 T hCV2744023 (rs369328) LETS addA_vs_G 0.002 1.35 1.11 1.63 A MEGA1 add A_vs_G 0.018 1.13 1.02 1.24 ALETS Gen AA_vs_GG 0.002 1.81 1.24 2.65 A Gen AG_vs_GG 0.072 1.34 0.971.84 A MEGA1 Gen AA_vs_GG 0.017 1.27 1.04 1.55 A Gen AG_vs_GG 0.367 1.080.91 1.28 A hCV27477533 (rs3756008) MEGA1 add T_vs_A 1E−06 1.28 1.161.42 T LETS add T_vs_A 0.031 1.22 1.02 1.46 T LETS Gen TA_vs_AA 0.0521.35 1 1.82 T Gen TT_vs_AA 0.044 1.46 1.01 2.11 T MEGA1 Gen TA_vs_AA0.001 1.31 1.11 1.53 T Gen TT_vs_AA 2E−06 1.63 1.33 2 T hCV949676(rs480802) MEGA1 Gen CC_vs_TT 0.027 1.44 1.04 1.99 C LETS Gen CC_vs_TT0.049 1.86 1 3.47 C LETS Gen CC_vs_TT 0.049 1.86 1 3.47 C Gen CT_vs_TT0.581 1.08 0.81 1.45 C MEGA1 Gen CC_vs_TT 0.027 1.44 1.04 1.99 C GenCT_vs_TT 0.519 1.05 0.9 1.23 C hCV27904396 (rs4829996) LETS recGG_vs_GA + AA 0.041 1.32 1.01 1.73 G MEGA1 Gen GA_vs_AA 0.049 1.26 11.58 G LETS Gen GA_vs_AA 0.917 1.02 0.67 1.57 G Gen GG_vs_AA 0.119 1.340.93 1.94 G MEGA1 Gen GA_vs_AA 0.049 1.26 1 1.58 G Gen GG_vs_AA 0.1151.17 0.96 1.41 G hCV837462 (rs528088) LETS Gen CC_vs_AA 0.071 4.2 0.8919.9 C MEGA1 dom AA + AC_vs_CC 0.027 3.05 1.14 8.18 A LETS Gen CA_vs_AA0.677 1.08 0.75 1.55 C Gen CC_vs_AA 0.071 4.2 0.89 19.9 C MEGA1 GenAA_vs_CC 0.027 3.04 1.13 8.16 A Gen AC_vs_CC 0.027 3.09 1.14 8.43 AhCV30440155 (rs6699146) LETS add C_vs_G 0.062 1.19 0.99 1.43 C MEGA1 addC_vs_G 0.003 1.16 1.05 1.28 C LETS Gen CC_vs_GG 0.063 1.42 0.98 2.05 CGen CG_vs_GG 0.29 1.18 0.87 1.59 C MEGA1 Gen CC_vs_GG 0.003 1.36 1.111.66 C Gen CG_vs_GG 0.276 1.1 0.93 1.3 C hCV28960679 (rs6844764) LETSrec GG_vs_GC + CC 0.072 1.29 0.98 1.71 G MEGA1 dom GG + GC_vs_CC 0.0071.28 1.07 1.54 G LETS Gen GC_vs_CC 0.976 0.99 0.69 1.43 G Gen GG_vs_CC0.203 1.29 0.87 1.9 G MEGA1 Gen GC_vs_CC 0.007 1.3 1.07 1.58 G GenGG_vs_CC 0.029 1.26 1.02 1.54 G hCV1952126 (rs7223784) LETS add A_vs_C0.026 1.26 1.03 1.55 A MEGA1 add A_vs_C 0.035 1.13 1.01 1.26 A LETS GenAA_vs_CC 0.08 1.56 0.95 2.56 A Gen AC_vs_CC 0.461 1.21 0.73 2.01 A MEGA1Gen AA_vs_CC 0.036 1.35 1.02 1.78 A Gen AC_vs_CC 0.143 1.24 0.93 1.65 AhCV31749285 (rs8178591) LETS rec CC_vs_CT + TT 0.069 1.28 0.98 1.66 CMEGA1 rec CC_vs_CT + TT 0.013 1.2 1.04 1.38 C LETS Gen CC_vs_TT 0.6150.88 0.53 1.45 C Gen CT_vs_TT 0.086 0.64 0.38 1.06 C MEGA1 Gen CC_vs_TT0.114 1.26 0.95 1.69 C Gen CT_vs_TT 0.666 1.07 0.79 1.44 C hCV3187716AGTR1 (rs5186

LETS dom CC + CA_vs_AA 0.096 1.25 0.96 1.63 C MEGA1 add A_vs_C 0.0021.19 1.06 1.33 A LETS Gen AA_vs_CC 0.292 0.77 0.48 1.25 A Gen AC_vs_CC0.782 0.93 0.58 1.51 A MEGA1 Gen AA_vs_CC 0.018 1.38 1.06 1.8 A GenAC_vs_CC 0.343 1.14 0.87 1.49 A hCV9493081

KT3 (rs105830

LETS add T_vs_C 4E−04 1.45 1.18 1.78 T MEGA1 add T_vs_C 0.008 1.16 1.041.29 T LETS Gen TC_vs_CC 0.004 1.5 1.13 1.98 T Gen TT_vs_CC 0.004 2.011.24 3.26 T MEGA1 Gen TC_vs_CC 0.922 1.01 0.87 1.17 T Gen TT_vs_CC 2E−041.62 1.25 2.09 T hCV30690780

T3 (rs1073788 LETS add C_vs_A 4E−05 1.58 1.27 1.96 C MEGA1 add C_vs_A0.001 1.21 1.08 1.36 C LETS Gen CA_vs_AA 9E−04 1.61 1.21 2.13 C GenCC_vs_AA 0.002 2.4 1.37 4.19 C MEGA1 Gen CA_vs_AA 0.256 1.09 0.94 1.27 CGen CC_vs_AA 1E−04 1.78 1.33 2.38 C hCV31523557

T3 (rs1075480 LETS add A_vs_G 2E−04 1.57 1.24 1.98 A MEGA1 add A_vs_G0.002 1.21 1.07 1.36 A LETS Gen AA_vs_GG 0.044 1.98 1.02 3.86 A GenAG_vs_GG 4E−04 1.68 1.26 2.25 A MEGA1 Gen AA_vs_GG 0.043 1.41 1.01 1.97A Gen AG_vs_GG 0.01 1.22 1.05 1.43 A hCV26719108

T3 (rs1092703 LETS add C_vs_T 0.002 1.36 1.12 1.66 C MEGA1 add C_vs_T0.002 1.18 1.06 1.3 C LETS Gen CC_vs_TT 0.004 1.84 1.21 2.8 C GenCT_vs_TT 0.027 1.38 1.04 1.83 C MEGA1 Gen CC_vs_TT 0.002 1.42 1.14 1.77C Gen CT_vs_TT 0.129 1.13 0.97 1.32 C hCV26719121

T3 (rs1092704 LETS add C_vs_T 1E−04 1.59 1.26 2 C MEGA1 add C_vs_T 0.0071.18 1.05 1.34 C LETS Gen CC_vs_TT 0.03 2.08 1.07 4.03 C Gen CT_vs_TT3E−04 1.69 1.27 2.26 C MEGA1 Gen CC_vs_TT 0.063 1.38 0.98 1.93 C GenCT_vs_TT 0.026 1.19 1.02 1.39 C hCV26719227

T3 (rs1092706 LETS add A_vs_C 0.01 1.4 1.08 1.8 A MEGA1 add A_vs_C 0.0131.18 1.04 1.34 A LETS Gen AA_vs_CC 0.458 1.38 0.59 3.25 A Gen AC_vs_CC0.007 1.5 1.12 2.01 A MEGA1 Gen AA_vs_CC 0.093 1.4 0.94 2.09 A GenAC_vs_CC 0.042 1.18 1.01 1.38 A hCV31523638

T3 (rs1203701 LETS add A_vs_G 0.003 1.49 1.15 1.93 A MEGA1 add A_vs_G0.021 1.18 1.02 1.35 A LETS Gen AA_vs_GG 0.317 1.57 0.65 3.77 A GenAG_vs_GG 0.002 1.6 1.18 2.17 A MEGA1 Gen AA_vs_GG 0.075 1.52 0.96 2.4 AGen AG_vs_GG 0.085 1.15 0.98 1.35 A hCV30690777

T3 (rs1204558 MEGA1 add A_vs_G 0.002 1.25 1.08 1.43 A LETS add A_vs_G0.035 1.32 1.02 1.72 A LETS Gen AA_vs_GG 0.36 1.54 0.61 3.88 A GenAG_vs_GG 0.045 1.36 1.01 1.83 A MEGA1 Gen AA_vs_GG 0.017 1.85 1.12 3.07A Gen AG_vs_GG 0.021 1.21 1.03 1.42 A hCV31523650

T3 (rs1204893 LETS add T_vs_C 1E−03 1.47 1.17 1.86 T MEGA1 add T_vs_C0.026 1.15 1.02 1.29 T LETS Gen TC_vs_CC 0.003 1.55 1.17 2.06 T GenTT_vs_CC 0.053 1.9 0.99 3.64 T MEGA1 Gen TC_vs_CC 0.032 1.18 1.01 1.38 TGen TT_vs_CC 0.228 1.22 0.88 1.7 T hCV30690778

T3 (rs1214041 LETS add C_vs_T 0.003 1.44 1.14 1.82 C MEGA1 add C_vs_T0.04 1.14 1.01 1.3 C LETS Gen CC_vs_TT 0.23 1.53 0.76 3.08 C GenCT_vs_TT 0.002 1.58 1.19 2.1 C MEGA1 Gen CC_vs_TT 0.027 1.54 1.05 2.26 CGen CT_vs_TT 0.283 1.09 0.93 1.27 C hCV31523608

T3 (rs1274429 MEGA1 add G_vs_A 0.001 1.19 1.07 1.32 G LETS add G_vs_A0.006 1.32 1.08 1.61 G LETS Gen GA_vs_AA 0.021 1.39 1.05 1.84 G GenGG_vs_AA 0.026 1.65 1.06 2.57 G MEGA1 Gen GA_vs_AA 0.013 1.21 1.04 1.41G Gen GG_vs_AA 0.004 1.39 1.11 1.75 G hCV233148

T3 (rs141712

LETS add C_vs_G 3E−04 1.45 1.18 1.78 C MEGA1 add C_vs_G 0.001 1.2 1.081.33 C LETS Gen CC_vs_GG 0.004 2.02 1.25 3.27 C Gen CG_vs_GG 0.004 1.51.14 1.98 C MEGA1 Gen CC_vs_GG 3E−05 1.71 1.33 2.2 C Gen CG_vs_GG 0.5911.04 0.9 1.21 C hCV12073840 AKT3 (rs14403) LETS Gen TC_vs_CC 0.004 1.51.14 1.98 T MEGA1 Gen TT_vs_CC 0.028 1.42 1.04 1.93 T LETS Gen TC_vs_CC0.004 1.5 1.14 1.98 T Gen TT_vs_CC 0.169 1.49 0.84 2.63 T MEGA1 GenTC_vs_CC 0.808 1.02 0.88 1.18 T Gen TT_vs_CC 0.028 1.42 1.04 1.93 ThCV1678674

KT3 (rs1458023 LETS add C_vs_T 4E−04 1.5 1.2 1.88 C MEGA1 add C_vs_T0.006 1.18 1.05 1.33 C LETS Gen CC_vs_TT 0.015 2.12 1.16 3.88 C GenCT_vs_TT 0.003 1.54 1.16 2.06 C MEGA1 Gen CC_vs_TT 0.057 1.37 0.99 1.88C Gen CT_vs_TT 0.021 1.2 1.03 1.4 C hCV97631

KT3 (rs1538773 LETS add G_vs_T 1E−04 1.55 1.24 1.92 G MEGA1 add G_vs_T0.006 1.18 1.05 1.32 G LETS Gen GG_vs_TT 0.009 2.14 1.21 3.77 G GenGT_vs_TT 6E−04 1.63 1.23 2.16 G MEGA1 Gen GG_vs_TT 0.003 1.59 1.18 2.14G Gen GT_vs_TT 0.224 1.1 0.94 1.28 G hCV8688111

KT3 (rs1578275 LETS add C_vs_G 0.001 1.49 1.17 1.89 C MEGA1 add C_vs_G0.047 1.14 1 1.29 C LETS Gen CC_vs_GG 0.064 2 0.96 4.18 C Gen CG_vs_GG0.004 1.53 1.15 2.04 C MEGA1 Gen CC_vs_GG 0.036 1.51 1.03 2.22 C GenCG_vs_GG 0.291 1.09 0.93 1.27 C hCV15885425

KT3 (rs229075

LETS add C_vs_A 1E−04 1.57 1.24 1.97 C MEGA1 add C_vs_A 0.019 1.15 1.021.3 C LETS Gen CA_vs_AA 0.001 1.62 1.21 2.15 C Gen CC_vs_AA 0.015 2.251.17 4.32 C MEGA1 Gen CA_vs_AA 0.026 1.19 1.02 1.39 C Gen CC_vs_AA 0.1841.24 0.9 1.72 C hCV1678682 AKT3 (rs320339 LETS add T_vs_G 3E−04 1.511.21 1.9 T MEGA1 add T_vs_G 0.002 1.21 1.07 1.37 T LETS Gen TG_vs_GG0.002 1.59 1.19 2.13 T Gen TT_vs_GG 0.021 2.04 1.11 3.75 T MEGA1 GenTG_vs_GG 0.04 1.18 1.01 1.37 T Gen TT_vs_GG 0.006 1.57 1.14 2.17 ThCV29210363

KT3 (rs6656918 LETS add G_vs_A 5E−05 1.56 1.26 1.94 G MEGA1 add G_vs_A0.003 1.19 1.06 1.34 G LETS Gen GA_vs_AA 6E−04 1.64 1.24 2.17 G GenGG_vs_AA 0.004 2.24 1.29 3.9 G MEGA1 Gen GA_vs_AA 0.289 1.09 0.93 1.26 GGen GG_vs_AA 4E−04 1.69 1.26 2.27 G hCV31523643

KT3 (rs6671475 LETS add G_vs_A 4E−04 1.52 1.21 1.91 G MEGA1 add G_vs_A0.014 1.16 1.03 1.31 G LETS Gen GA_vs_AA 0.003 1.55 1.16 2.06 G GenGG_vs_AA 0.018 2.2 1.14 4.22 G MEGA1 Gen GA_vs_AA 0.038 1.18 1.01 1.37 GGen GG_vs_AA 0.1 1.32 0.95 1.82 G hCV26719113

KT3 (rs751734

LETS add T_vs_C 2E−04 1.58 1.24 2 T MEGA1 add T_vs_C 0.003 1.2 1.07 1.36T LETS Gen TC_vs_CC 2E−04 1.76 1.31 2.36 T Gen TT_vs_CC 0.061 1.87 0.973.59 T MEGA1 Gen TC_vs_CC 0.074 1.15 0.99 1.35 T Gen TT_vs_CC 0.005 1.621.15 2.27 T hCV26034142

KT3 (rs9428576 LETS add C_vs_T 0.025 1.23 1.03 1.47 C MEGA1 recCC_vs_CT + TT 0.01 1.26 1.06 1.49 C LETS Gen CC_vs_TT 0.029 1.49 1.042.15 C Gen CT_vs_TT 0.067 1.33 0.98 1.81 C MEGA1 Gen CC_vs_TT 0.066 1.210.99 1.48 C Gen CT_vs_TT 0.454 0.94 0.8 1.11 C hCV2303891 POH (rs180169

MEGA1 add C_vs_G 0.007 1.38 1.09 1.76 C LETS add C_vs_G 0.042 1.65 1.022.68 C LETS Gen CC_vs_GG 0.969 291630 #### #### C Gen CG_vs_GG 0.97188937 #### #### C MEGA1 Gen CC_vs_GG 0.528 0.62 0.14 2.76 C GenCG_vs_GG 0.263 0.42 0.09 1.92 C hCV2456747 orf114 (rs38200 MEGA1 addA_vs_G 1E−04 1.22 1.1 1.35 A LETS add A_vs_G 0.004 1.34 1.1 1.64 A LETSGen AA_vs_GG 0.035 1.61 1.03 2.51 A Gen AG_vs_GG 0.005 1.49 1.13 1.98 AMEGA1 Gen AA_vs_GG 1E−03 1.45 1.16 1.8 A Gen AG_vs_GG 0.002 1.27 1.091.48 A hCV2403368 QTNF6 (rs2295

LETS rec GG_vs_GC + CC 0.02 1.37 1.05 1.79 G MEGA1 rec GG_vs_GC + CC0.033 1.17 1.01 1.35 G LETS Gen GC_vs_CC 0.521 0.82 0.46 1.49 G GenGG_vs_CC 0.615 1.16 0.65 2.06 G MEGA1 Gen GC_vs_CC 0.911 0.98 0.72 1.35G Gen GG_vs_CC 0.371 1.15 0.85 1.56 G hCV7574127 orf167 (rs17371 LETSadd A_vs_G 0.091 1.18 0.97 1.43 A MEGA1 add A_vs_G 0.009 1.14 1.03 1.26A LETS Gen AA_vs_GG 0.097 1.38 0.94 2.03 A Gen AG_vs_GG 0.414 1.16 0.821.64 A MEGA1 Gen AA_vs_GG 0.01 1.3 1.07 1.58 A Gen AG_vs_GG 0.164 1.140.95 1.36 A hCV25959498 orf46 (rs345186 LETS add G_vs_A 0.034 1.48 1.032.14 G MEGA1 add G_vs_A 0.038 1.22 1.01 1.47 G LETS Gen GA_vs_AA 0.1664.57 0.53 39.2 G Gen GG_vs_AA 0.093 6.16 0.74 51.3 G MEGA1 Gen GA_vs_AA0.159 1.98 0.77 5.12 G Gen GG_vs_AA 0.079 2.31 0.91 5.88 G hCV25959466orf46 (rs354955 MEGA1 add T_vs_C 0.03 1.23 1.02 1.48 T LETS add T_vs_C0.048 1.45 1 2.1 T LETS Gen TC_vs_CC 0.229 3.81 0.43 33.7 T Gen TT_vs_CC0.137 5.12 0.6 44 T MEGA1 Gen TC_vs_CC 0.206 1.78 0.73 4.35 T GenTT_vs_CC 0.096 2.11 0.88 5.06 T hCV25768636

DC36 (rs42791

MEGA1 rec AA_vs_AG + GG 0.033 1.26 1.02 1.56 A LETS rec AA_vs_AG + GG0.036 1.53 1.03 2.27 A LETS Gen AA_vs_GG 0.022 1.63 1.07 2.49 A GenAG_vs_GG 0.359 1.14 0.86 1.51 A MEGA1 Gen AA_vs_GG 0.033 1.28 1.02 1.61A Gen AG_vs_GG 0.698 1.03 0.89 1.2 A hCV25991132 CCDC41 ( ) MEGA1 recGG_vs_GA + AA 0.018 1.26 1.04 1.53 G LETS rec GG_vs_GA + AA 0.041 1.461.02 2.1 G LETS Gen GA_vs_AA 0.236 3.72 0.42 32.7 G Gen GG_vs_AA 0.1345.19 0.6 44.6 G MEGA1 Gen GA_vs_AA 0.013 0.29 0.11 0.77 G Gen GG_vs_AA0.052 0.38 0.14 1.01 G hCV3164397

YA5 (rs100439

LETS rec CC_vs_CT + TT 0.004 1.55 1.15 2.08 C MEGA1 dom CC + CT_vs_TT0.015 2.28 1.18 4.42 C LETS Gen CC_vs_TT 0.959 0.98 0.37 2.56 C GenCT_vs_TT 0.323 0.61 0.23 1.63 C MEGA1 Gen CC_vs_TT 0.017 2.24 1.16 4.35C Gen CT_vs_TT 0.01 2.41 1.23 4.73 C hCV3230083 P4V2 (rs100136 MEGA1 GenAC_vs_CC 4E−04 1.35 1.14 1.59 A LETS Gen AC_vs_CC 0.048 1.37 1 1.86 ALETS Gen AA_vs_CC 0.342 1.2 0.83 1.74 A Gen AC_vs_CC 0.048 1.37 1 1.86 AMEGA1 Gen AA_vs_CC 0.002 1.39 1.13 1.7 A Gen AC_vs_CC 4E−04 1.35 1.141.59 A hCV25990131 P4V2 (rs131462 MEGA1 add A_vs_C 0.001 1.19 1.07 1.32A LETS add A_vs_C 0.049 1.22 1 1.49 A LETS Gen AA_vs_CC 0.003 2.03 1.273.24 A Gen AC_vs_CC 0.001 2.18 1.36 3.48 A MEGA1 Gen AA_vs_CC 0.006 1.381.1 1.74 A Gen AC_vs_CC 0.251 1.15 0.91 1.44 A hCV15968043

P4V2 (rs22924

MEGA1 dom AA + AT_vs_TT 2E−04 1.33 1.14 1.55 A LETS dom AA + AT_vs_TT0.043 1.34 1.01 1.78 A LETS Gen AA_vs_TT 0.14 1.32 0.91 1.92 A GenAT_vs_TT 0.052 1.35 1 1.83 A MEGA1 Gen AA_vs_TT 1E−04 1.49 1.21 1.83 AGen AT_vs_TT 0.003 1.27 1.08 1.5 A hCV3230096

P4V2 (rs38171

LETS dom TT + TC_vs_CC 0.058 1.32 0.99 1.76 T MEGA1 dom TT + TC_vs_CC0.003 1.26 1.08 1.47 T LETS Gen TC_vs_CC 0.063 1.34 0.98 1.81 T GenTT_vs_CC 0.193 1.28 0.88 1.86 T MEGA1 Gen TC_vs_CC 0.027 1.2 1.02 1.41 TGen TT_vs_CC 5E−04 1.43 1.17 1.75 T hCV11786147

P4V2 (rs48626

LETS dom TT + TG_vs_GG 0.052 1.33 1 1.77 T MEGA1 dom TT + TG_vs_GG 0.0031.26 1.09 1.47 T LETS Gen TG_vs_GG 0.06 1.34 0.99 1.82 T Gen TT_vs_GG0.164 1.31 0.9 1.9 T MEGA1 Gen TG_vs_GG 0.018 1.22 1.03 1.43 T GenTT_vs_GG 0.001 1.4 1.14 1.72 T hCV3230084

P4V2 (rs76829

MEGA1 Gen TC_vs_CC 0.002 1.29 1.1 1.51 T LETS Gen TC_vs_CC 0.031 1.391.03 1.88 T LETS Gen TC_vs_CC 0.031 1.39 1.03 1.88 T Gen TT_vs_CC 0.7921.05 0.71 1.55 T MEGA1 Gen TC_vs_CC 0.002 1.29 1.1 1.51 T Gen TT_vs_CC0.009 1.32 1.07 1.63 T hCV26265231

P4V2 (rs76840

MEGA1 dom AA + AG_vs_GG 8E−04 1.32 1.12 1.55 A LETS dom AA + AG_vs_GG0.017 1.44 1.07 1.95 A LETS Gen AA_vs_GG 0.114 1.34 0.93 1.94 A GenAG_vs_GG 0.013 1.5 1.09 2.07 A MEGA1 Gen AA_vs_GG 6E−04 1.43 1.16 1.75 AGen AG_vs_GG 0.006 1.27 1.07 1.51 A hCV9860072 HX38 (rs105036 LETS GenAC_vs_CC 0.013 1.43 1.08 1.91 A MEGA1 Gen AA_vs_CC 0.042 1.26 1.01 1.57A LETS Gen AA_vs_CC 0.289 1.25 0.83 1.88 A Gen AC_vs_CC 0.013 1.43 1.081.91 A MEGA1 Gen AA_vs_CC 0.042 1.26 1.01 1.57 A Gen AC_vs_CC 0.385 1.070.92 1.25 A hCV2103346

564J102 (rs117 LETS rec CC_vs_CT + TT 0.016 1.5 1.08 2.08 C MEGA1 domCC + CT_vs_TT 0.021 1.2 1.03 1.4 C LETS Gen CC_vs_TT 0.108 1.36 0.941.98 C Gen CT_vs_TT 0.286 0.85 0.63 1.15 C MEGA1 Gen CC_vs_TT 0.036 1.241.01 1.52 C Gen CT_vs_TT 0.045 1.18 1 1.4 C hCV12086148

564J102 (rs18

LETS rec GG_vs_GA + AA 0.065 1.29 0.98 1.69 G MEGA1 Gen GG_vs_AA 0.0271.47 1.04 2.06 G LETS Gen GA_vs_AA 0.613 0.86 0.47 1.56 G Gen GG_vs_AA0.69 1.13 0.63 2.02 G MEGA1 Gen GA_vs_AA 0.056 1.4 0.99 1.99 G GenGG_vs_AA 0.027 1.47 1.04 2.06 G hCV25473516

SP11 (rs22720

LETS Gen TT_vs_CC 0.074 1.46 0.96 2.22 T MEGA1 Gen TT_vs_CC 0.011 1.331.07 1.67 T LETS Gen TC_vs_CC 0.698 1.06 0.8 1.41 T Gen TT_vs_CC 0.0741.46 0.96 2.22 T MEGA1 Gen TC_vs_CC 0.355 1.07 0.92 1.25 T Gen TT_vs_CC0.011 1.33 1.07 1.67 T hCV15871021

BF1 (rs207249

LETS rec GG_vs_GA + AA 0.013 1.41 1.08 1.86 G MEGA1 dom GG + GA_vs_AA0.007 1.33 1.08 1.63 G LETS Gen GA_vs_AA 0.157 0.76 0.51 1.11 G GenGG_vs_AA 0.506 1.15 0.77 1.71 G MEGA1 Gen GA_vs_AA 0.008 1.34 1.08 1.67G Gen GG_vs_AA 0.019 1.31 1.04 1.64 G hCV491830

S8L2 (rs30875

LETS add T_vs_C 0.018 1.26 1.04 1.52 T MEGA1 add T_vs_C 0.027 1.12 1.011.24 T LETS Gen TC_vs_CC 0.437 1.15 0.81 1.65 T Gen TT_vs_CC 0.026 1.541.05 2.26 T MEGA1 Gen TC_vs_CC 0.041 1.22 1.01 1.49 T Gen TT_vs_CC 0.0171.28 1.04 1.57 T hCV2017876

S8L3 (rs38185

LETS add G_vs_A 0.069 1.18 0.99 1.42 G MEGA1 add G_vs_A 0.025 1.12 1.011.24 G LETS Gen GA_vs_AA 0.572 1.1 0.79 1.54 G Gen GG_vs_AA 0.077 1.390.97 1.99 G MEGA1 Gen GA_vs_AA 0.498 1.07 0.89 1.28 G Gen GG_vs_AA 0.031.25 1.02 1.53 G hCV12066124 F11 (rs2036914 MEGA1 add C_vs_T 2E−07 1.311.18 1.44 C LETS add C_vs_T 0.013 1.27 1.05 1.53 C LETS Gen CC_vs_TT0.01 1.65 1.13 2.42 C Gen CT_vs_TT 0.053 1.43 1 2.05 C MEGA1 GenCC_vs_TT 2E−07 1.73 1.41 2.12 C Gen CT_vs_TT 9E−04 1.38 1.14 1.66 ChCV16172935 F11 (rs2241817 LETS rec AA_vs_AG + GG 0.075 1.27 0.98 1.66 AMEGA1 rec AA_vs_AG + GG 0.032 1.17 1.01 1.35 A LETS Gen AA_vs_GG 0.9620.99 0.64 1.54 A Gen AG_vs_GG 0.167 0.73 0.47 1.14 A MEGA1 Gen AA_vs_GG0.01 1.37 1.08 1.74 A Gen AG_vs_GG 0.102 1.22 0.96 1.54 A hCV3230038 F11(rs2289252 LETS add T_vs_C 0.061 1.19 0.99 1.42 T MEGA1 add T_vs_C #####1.34 1.21 1.48 T LETS Gen TC_vs_CC 0.165 1.24 0.92 1.68 T Gen TT_vs_CC0.069 1.4 0.97 2.01 T MEGA1 Gen TC_vs_CC 2E−05 1.43 1.21 1.69 T GenTT_vs_CC 4E−08 1.78 1.45 2.18 T hCV27474895 F11 (rs3756011 MEGA1 addA_vs_C ##### 1.32 1.19 1.46 A LETS add A_vs_C 0.035 1.21 1.01 1.45 ALETS Gen AA_vs_CC 0.043 1.45 1.01 2.09 A Gen AC_vs_CC 0.089 1.3 0.961.76 A MEGA1 Gen AA_vs_CC 1E−07 1.73 1.41 2.12 A Gen AC_vs_CC 2E−04 1.371.16 1.61 A hCV25474413 F11 (rs3822057 LETS Gen CC_vs_AA 0.061 1.42 0.982.05 C MEGA1 Gen CC_vs_AA 2E−06 1.63 1.33 2 C LETS Gen CA_vs_AA 0.1461.28 0.92 1.79 C Gen CC_vs_AA 0.061 1.42 0.98 2.05 C MEGA1 Gen CA_vs_AA0.002 1.34 1.12 1.6 C Gen CC_vs_AA 2E−06 1.63 1.33 2 C hCV27490984 F11(rs3822058 LETS rec GG_vs_GA + AA 0.076 1.27 0.98 1.66 G MEGA1 recGG_vs_GA + AA 0.022 1.18 1.02 1.36 G LETS Gen GA_vs_AA 0.108 0.7 0.451.08 G Gen GG_vs_AA 0.831 0.95 0.61 1.48 G MEGA1 Gen GA_vs_AA 0.059 1.260.99 1.6 G Gen GG_vs_AA 0.004 1.42 1.12 1.81 G hCV25474414 F11(rs4253399 MEGA1 add G_vs_T 5E−07 1.3 1.17 1.44 G LETS add G_vs_T 0.0231.23 1.03 1.48 G LETS Gen GG_vs_TT 0.038 1.48 1.02 2.15 G Gen GT_vs_TT0.049 1.35 1 1.81 G MEGA1 Gen GG_vs_TT 6E−07 1.7 1.38 2.09 G GenGT_vs_TT 0.003 1.28 1.09 1.5 G hCV26038139 F11 (rs4253405 MEGA1 GenAG_vs_GG 0.006 1.39 1.1 1.74 A LETS Gen AG_vs_GG 0.048 0.66 0.43 1 ALETS Gen AA_vs_GG 0.767 0.94 0.62 1.43 A Gen AG_vs_GG 0.048 0.66 0.43 1A MEGA1 Gen AA_vs_GG 3E−04 1.54 1.22 1.95 A Gen AG_vs_GG 0.006 1.39 1.11.74 A hCV3230119 F11 (rs4253430 LETS rec GG_vs_GC + CC 0.052 1.3 1 1.7G MEGA1 rec GG_vs_GC + CC 0.038 1.16 1.01 1.34 G LETS Gen GC_vs_CC 0.2220.76 0.49 1.18 G Gen GG_vs_CC 0.845 1.04 0.67 1.62 G MEGA1 Gen GC_vs_CC0.062 1.25 0.99 1.59 G Gen GG_vs_CC 0.006 1.4 1.1 1.77 G hCV8241630 F11(rs925451) MEGA1 add A_vs_G ##### 1.32 1.2 1.46 A LETS add A_vs_G 0.0451.2 1 1.44 A LETS Gen AA_vs_GG 0.078 1.39 0.96 2.01 A Gen AG_vs_GG 0.0291.39 1.03 1.88 A MEGA1 Gen AA_vs_GG 1E−07 1.75 1.42 2.15 A Gen AG_vs_GG3E−04 1.34 1.14 1.57 A hCV8726802 F2 (rs1799963) MEGA1 add A_vs_G 2E−072.85 1.92 4.24 A LETS add A_vs_G 0.003 3 1.44 6.26 A LETS Gen AG_vs_GG0.003 3 1.44 6.26 A MEGA1 Gen AG_vs_GG 2E−07 2.85 1.92 4.24 AhCV27480803 F5 (rs3766103) MEGA1 add C_vs_T 4E−04 1.2 1.08 1.32 C LETSadd C_vs_T 0.017 1.26 1.04 1.52 C LETS Gen CC_vs_TT 0.015 1.61 1.1 2.36C Gen CT_vs_TT 0.25 1.19 0.88 1.61 C MEGA1 Gen CC_vs_TT 3E−04 1.44 1.181.75 C Gen CT_vs_TT 0.107 1.15 0.97 1.35 C hCV8919444 F5 (rs4524) MEGA1add T_vs_C 1E−04 1.26 1.12 1.42 T LETS add T_vs_C 0.006 1.36 1.09 1.69 TLETS Gen TC_vs_CC 0.931 1.03 0.58 1.83 T Gen TT_vs_CC 0.13 1.54 0.882.68 T MEGA1 Gen TC_vs_CC 0.565 0.91 0.66 1.25 T Gen TT_vs_CC 0.124 1.270.94 1.73 T hCV8919442 F5 (rs4525) MEGA1 add T_vs_C 5E−05 1.28 1.14 1.44T LETS add T_vs_C 0.01 1.33 1.07 1.66 T LETS Gen TC_vs_CC 0.846 0.940.53 1.68 T Gen TT_vs_CC 0.216 1.42 0.82 2.47 T MEGA1 Gen TC_vs_CC 0.5620.91 0.66 1.25 T Gen TT_vs_CC 0.103 1.29 0.95 1.77 T hCV8919451 F5(rs6016) MEGA1 add G_vs_A 6E−05 1.27 1.13 1.43 G LETS add G_vs_A 0.0061.35 1.09 1.69 G LETS Gen GA_vs_AA 0.967 0.99 0.55 1.76 G Gen GG_vs_AA0.163 1.49 0.85 2.6 G MEGA1 Gen GA_vs_AA 0.414 0.88 0.64 1.2 G GenGG_vs_AA 0.141 1.26 0.93 1.71 G hCV2288095 F9 (rs378815) LETS GenCC_vs_TT 0.02 1.5 1.07 2.11 C MEGA1 Gen CT_vs_TT 0.048 1.23 1 1.52 CLETS Gen CC_vs_TT 0.02 1.5 1.07 2.11 C Gen CT_vs_TT 0.282 1.24 0.84 1.82C MEGA1 Gen CC_vs_TT 0.177 1.13 0.95 1.34 C Gen CT_vs_TT 0.048 1.23 11.52 C hCV596326 F9 (rs398101) LETS rec AA_vs_AG + GG 0.006 1.46 1.121.9 A MEGA1 Gen AG_vs_GG 0.015 1.31 1.05 1.64 A LETS Gen AA_vs_GG 0.061.4 0.99 1.99 A Gen AG_vs_GG 0.729 0.93 0.62 1.4 A MEGA1 Gen AA_vs_GG0.067 1.19 0.99 1.42 A Gen AG_vs_GG 0.015 1.31 1.05 1.64 A hCV596330 F9(rs422187) LETS add A_vs_C 0.048 1.19 1 1.41 A MEGA1 add A_vs_C 0.0491.09 1 1.2 A LETS Gen AA_vs_CC 0.085 1.37 0.96 1.96 A Gen AC_vs_CC 0.7571.07 0.71 1.61 A MEGA1 Gen AA_vs_CC 0.016 1.26 1.04 1.51 A Gen AC_vs_CC0.008 1.35 1.08 1.68 A hCV596331 F9 (rs6048) LETS rec AA_vs_AG + GG0.016 1.39 1.06 1.81 A MEGA1 dom AA + AG_vs_GG 0.014 1.26 1.05 1.51 ALETS Gen AA_vs_GG 0.069 1.4 0.97 2 A Gen AG_vs_GG 0.968 1.01 0.67 1.52 AMEGA1 Gen AA_vs_GG 0.023 1.24 1.03 1.5 A Gen AG_vs_GG 0.024 1.3 1.041.63 A hCV2892877 FGA (rs6050) LETS add C_vs_T 0.058 1.29 0.99 1.68 CMEGA1 add C_vs_T 5E−07 1.44 1.25 1.66 C LETS Gen CT_vs_TT 0.058 1.290.99 1.68 C MEGA1 Gen CT_vs_TT 5E−07 1.44 1.25 1.66 C hCV11503469

GG (rs2066854 MEGA1 add A_vs_T ##### 1.41 1.26 1.57 A LETS add A_vs_T2E−04 1.48 1.2 1.83 A LETS Gen AA_vs_TT 5E−05 3.01 1.77 5.11 A GenAT_vs_TT 0.139 1.23 0.93 1.62 A MEGA1 Gen AA_vs_TT 8E−08 1.96 1.53 2.5 AGen AT_vs_TT 4E−06 1.42 1.22 1.65 A hCV11503414

GG (rs2066865 MEGA1 add A_vs_G ##### 1.41 1.27 1.57 A LETS add A_vs_G4E−04 1.45 1.18 1.78 A LETS Gen AA_vs_GG 8E−05 2.81 1.68 4.7 A GenAG_vs_GG 0.215 1.19 0.9 1.57 A MEGA1 Gen AA_vs_GG 9E−08 1.97 1.54 2.53 AGen AG_vs_GG 5E−06 1.42 1.22 1.65 A hCV30505633 GNG12 (rs753053 LETS addT_vs_C 0.023 1.52 1.06 2.17 T MEGA1 add T_vs_C 0.047 1.2 1 1.44 T LETSGen TC_vs_CC 0.078 1.42 0.96 2.09 T Gen TT_vs_CC 0.124 5.42 0.63 46.6 TMEGA1 Gen TC_vs_CC 0.128 1.17 0.96 1.43 T Gen TT_vs_CC 0.151 1.74 0.823.68 T hCV8717873 GP6 (rs1613662 MEGA1 add A_vs_G 0.004 1.21 1.06 1.38 ALETS add A_vs_G 0.013 1.36 1.07 1.74 A LETS Gen AA_vs_GG 0.07 2.06 0.944.51 A Gen AG_vs_GG 0.282 1.55 0.7 3.47 A MEGA1 Gen AA_vs_GG 0.449 1.160.78 1.73 A Gen AG_vs_GG 0.62 0.9 0.6 1.36 A hCV1376342 GP6 (rs1654416LETS Gen TT_vs_CC 0.076 1.81 0.94 3.49 T MEGA1 rec TT_vs_TC + CC 0.0091.22 1.05 1.42 T LETS Gen TC_vs_CC 0.182 1.59 0.81 3.13 T Gen TT_vs_CC0.076 1.81 0.94 3.49 T MEGA1 Gen TC_vs_CC 0.647 0.91 0.62 1.35 T GenTT_vs_CC 0.545 1.12 0.77 1.64 T hCV8717893 GP6 (rs1671192 LETS GenGG_vs_AA 0.077 1.81 0.94 3.48 G MEGA1 rec GG_vs_GA + AA 0.004 1.24 1.071.44 G LETS Gen GA_vs_AA 0.182 1.59 0.81 3.13 G Gen GG_vs_AA 0.077 1.810.94 3.48 G MEGA1 Gen GA_vs_AA 0.395 0.84 0.57 1.25 G Gen GG_vs_AA 0.7291.07 0.73 1.56 G hCV2575036 RB10 (rs344327 LETS add A_vs_G 0.007 3.031.35 6.81 A MEGA1 add G_vs_A 0.025 1.49 1.05 2.11 G LETS Gen AG_vs_GG0.007 0.33 0.15 0.74 A MEGA1 Gen GA_vs_AA 0.038 1.45 1.02 2.07 G GenGG_vs_AA 0.952 137573 0 #### G hCV2699725 CY1B2 (rs11841 LETS GenCG_vs_GG 0.037 1.85 1.04 3.31 C MEGA1 Gen GC_vs_CC 0.048 1.33 1 1.78 GLETS Gen CC_vs_GG 0.314 3.2 0.33 30.9 C Gen CG_vs_GG 0.037 1.85 1.043.31 C MEGA1 Gen GC_vs_CC 0.048 1.33 1 1.78 G Gen GG_vs_CC 0.97 1.030.27 3.83 G hCV25995678 hCV25995678 LETS add T_vs_C 0.019 1.46 1.06 2 TMEGA1 dom TT + TC_vs_CC 0.049 2.73 1 7.42 T LETS Gen TC_vs_CC 0.569 1.440.41 4.98 T Gen TT_vs_CC 0.229 2.1 0.63 7.04 T MEGA1 Gen TC_vs_CC 0.0522.72 0.99 7.5 T Gen TT_vs_CC 0.049 2.73 1 7.42 T hCV25996277 hCV25996277LETS add A_vs_T 0.024 1.43 1.05 1.96 A MEGA1 Gen AA_vs_TT 0.021 3.191.19 8.51 A LETS Gen AA_vs_TT 0.231 2.09 0.63 7.02 A Gen AT_vs_TT 0.5471.47 0.42 5.08 A MEGA1 Gen AA_vs_TT 0.021 3.19 1.19 8.51 A Gen AT_vs_TT0.025 3.13 1.16 8.48 A hCV31199195 TD10 (rs108502 LETS dom CC + CA_vs_AA0.021 1.4 1.05 1.86 C MEGA1 dom CC + CA_vs_AA 0.036 1.17 1.01 1.37 CLETS Gen CA_vs_AA 0.013 1.45 1.08 1.95 C Gen CC_vs_AA 0.945 0.97 0.442.14 C MEGA1 Gen CA_vs_AA 0.065 1.16 0.99 1.35 C Gen CC_vs_AA 0.155 1.330.9 1.97 C hCV27502514

LF3 (rs379653

MEGA1 dom AA + AG_vs_GG 0.026 1.19 1.02 1.38 A LETS dom AA + AG_vs_GG0.038 1.34 1.02 1.77 A LETS Gen AA_vs_GG 0.499 1.28 0.63 2.61 A GenAG_vs_GG 0.042 1.35 1.01 1.8 A MEGA1 Gen AA_vs_GG 0.218 1.31 0.85 2 AGen AG_vs_GG 0.042 1.18 1.01 1.38 A hCV11786258 _KB1 (rs425330 LETS GenAG_vs_GG 0.069 1.32 0.98 1.78 A MEGA1 Gen AG_vs_GG 0.003 1.27 1.09 1.49A LETS Gen AA_vs_GG 0.32 1.21 0.83 1.78 A Gen AG_vs_GG 0.069 1.32 0.981.78 A MEGA1 Gen AA_vs_GG 4E−04 1.45 1.18 1.79 A Gen AG_vs_GG 0.003 1.271.09 1.49 A hCV540410 ASP1 (rs60952

LETS Gen AT_vs_TT 0.058 1.5 0.99 2.28 A MEGA1 Gen AA_vs_TT 0.009 3.831.39 10.6 A LETS Gen AA_vs_TT 0.47 0.53 0.1 2.93 A Gen AT_vs_TT 0.0581.5 0.99 2.28 A MEGA1 Gen AA_vs_TT 0.009 3.83 1.39 10.6 A Gen AT_vs_TT0.637 1.05 0.85 1.3 A hDV70662128 129656 (rs1704

LETS add A_vs_G 0.063 1.68 0.97 2.92 A MEGA1 add A_vs_G 9E−04 1.59 1.212.09 A LETS Gen AG_vs_GG 0.063 1.68 0.97 2.92 A MEGA1 Gen AA_vs_GG 0.4651.63 0.44 6.1 A Gen AG_vs_GG 9E−04 1.65 1.23 2.23 A hCV11541681 200420(rs2001 MEGA1 add C_vs_G 0.013 1.14 1.03 1.26 C LETS add C_vs_G 0.0391.22 1.01 1.49 C LETS Gen CC_vs_GG 0.028 1.57 1.05 2.35 C Gen CG_vs_GG0.441 1.12 0.84 1.5 C MEGA1 Gen CC_vs_GG 0.015 1.3 1.05 1.61 C GenCG_vs_GG 0.126 1.13 0.97 1.32 C hCV2706410 387646 (rs7896 LETS GenCT_vs_TT 0.015 1.41 1.07 1.87 C MEGA1 Gen CT_vs_TT 0.04 1.17 1.01 1.36 CLETS Gen CC_vs_TT 0.33 1.3 0.77 2.19 C Gen CT_vs_TT 0.015 1.41 1.07 1.87C MEGA1 Gen CC_vs_TT 0.817 0.97 0.72 1.29 C Gen CT_vs_TT 0.04 1.17 1.011.36 C hCV1547677 646030 (rs6505 LETS add G_vs_A 0.024 2.6 1.13 5.97 GMEGA1 add G_vs_A 0.044 1.37 1.01 1.87 G LETS Gen GA_vs_AA 0.024 2.6 1.135.97 G MEGA1 Gen GA_vs_AA 0.737 1.08 0.7 1.66 G Gen GG_vs_AA 0.015 3.241.25 8.38 G hCV8827309 728221 (rs1110 LETS add T_vs_C 0.006 1.49 1.121.98 T MEGA1 add T_vs_C 0.04 1.17 1.01 1.36 T LETS Gen TC_vs_CC 0.0211.46 1.06 2.02 T Gen TT_vs_CC 0.093 2.49 0.86 7.26 T MEGA1 Gen TC_vs_CC0.031 1.2 1.02 1.42 T Gen TT_vs_CC 0.658 1.14 0.63 2.06 T hCV2103392728284 (rs1250

LETS dom CC + CT_vs_TT 0.097 1.4 0.94 2.07 C MEGA1 dom CC + CT_vs_TT0.014 1.31 1.06 1.62 C LETS Gen CC_vs_TT 0.124 1.39 0.91 2.11 C GenCT_vs_TT 0.113 1.4 0.92 2.13 C MEGA1 Gen CC_vs_TT 0.005 1.39 1.11 1.75 CGen CT_vs_TT 0.064 1.24 0.99 1.55 C hCV3230136 728284 (rs1311

MEGA1 rec GG_vs_GA + AA 0.007 1.21 1.05 1.4 G LETS rec GG_vs_GA + AA0.03 1.34 1.03 1.75 G LETS Gen GA_vs_AA 0.415 0.8 0.46 1.37 G GenGG_vs_AA 0.7 1.11 0.65 1.88 G MEGA1 Gen GA_vs_AA 0.11 1.28 0.95 1.74 GGen GG_vs_AA 0.008 1.51 1.12 2.03 G hCV3230131 728284 (rs1313

LETS rec TT_vs_TC + CC 0.05 1.3 1 1.7 T MEGA1 rec TT_vs_TC + CC 0.0031.24 1.08 1.43 T LETS Gen TC_vs_CC 0.47 0.82 0.48 1.41 T Gen TT_vs_CC0.721 1.1 0.65 1.87 T MEGA1 Gen TC_vs_CC 0.067 1.33 0.98 1.8 T GenTT_vs_CC 0.003 1.59 1.18 2.14 T hCV29821005 728284 (rs6552 LETS GenTC_vs_CC 0.055 1.31 0.99 1.74 T MEGA1 Gen TC_vs_CC 0.008 1.23 1.05 1.43T LETS Gen TC_vs_CC 0.055 1.31 0.99 1.74 T Gen TT_vs_CC 0.59 1.2 0.622.29 T MEGA1 Gen TC_vs_CC 0.008 1.23 1.05 1.43 T Gen TT_vs_CC 0.491 1.130.8 1.6 T hCV32209621 728284 (rs6552 LETS Gen AG_vs_GG 0.054 1.39 0.991.94 A MEGA1 Gen AA_vs_GG 0.045 1.23 1 1.5 A LETS Gen AA_vs_GG 0.46 1.150.79 1.66 A Gen AG_vs_GG 0.054 1.39 0.99 1.94 A MEGA1 Gen AA_vs_GG 0.0451.23 1 1.5 A Gen AG_vs_GG 0.109 1.16 0.97 1.38 A hCV32209620 728284(rs6552 LETS dom CC + CT_vs_TT 0.061 1.29 0.99 1.69 C MEGA1 dom CC +CT_vs_TT 0.011 1.21 1.05 1.4 C LETS Gen CC_vs_TT 0.487 1.24 0.67 2.3 CGen CT_vs_TT 0.066 1.3 0.98 1.72 C MEGA1 Gen CC_vs_TT 0.462 1.14 0.811.61 C Gen CT_vs_TT 0.011 1.22 1.05 1.42 C hCV916107

729138 (rs670

LETS add C_vs_T 0.018 1.27 1.04 1.54 C MEGA1 add C_vs_T 0.026 1.13 1.011.25 C LETS Gen CC_vs_TT 0.022 1.67 1.08 2.6 C Gen CT_vs_TT 0.158 1.380.88 2.14 C MEGA1 Gen CC_vs_TT 0.012 1.35 1.07 1.7 C Gen CT_vs_TT 0.0351.28 1.02 1.61 C hCV30922162 729672 (rs4334 LETS add T_vs_C 0.013 1.31.06 1.6 T MEGA1 add T_vs_C 0.048 1.12 1 1.25 T LETS Gen TC_vs_CC 0.31.16 0.88 1.52 T Gen TT_vs_CC 0.006 2 1.22 3.29 T MEGA1 Gen TC_vs_CC0.355 1.07 0.92 1.24 T Gen TT_vs_CC 0.035 1.32 1.02 1.72 T hCV7504118

729672 (rs967

MEGA1 add G_vs_A 0.022 1.14 1.02 1.27 G LETS add G_vs_A 0.028 1.26 1.021.55 G LETS Gen GA_vs_AA 0.222 1.19 0.9 1.56 G Gen GG_vs_AA 0.029 1.751.06 2.91 G MEGA1 Gen GA_vs_AA 0.229 1.09 0.94 1.27 G Gen GG_vs_AA 0.0191.38 1.06 1.81 G hCV11633415

730144 (rs4262 MEGA1 add T_vs_C 0.003 1.34 1.1 1.64 T LETS add T_vs_C0.036 1.49 1.03 2.15 T LETS Gen TC_vs_CC 0.974 2E+06 0 Inf T GenTT_vs_CC 0.974 2E+06 0 Inf T MEGA1 Gen TC_vs_CC 0.842 1.11 0.4 3.06 TGen TT_vs_CC 0.416 1.51 0.56 4.1 T hCV2494846 JZP1 (rs376540 MEGA1 recGG_vs_GT + TT 0.029 1.56 1.05 2.33 G LETS rec GG_vs_GT + TT 0.043 2.21.03 4.74 G LETS Gen GG_vs_TT 0.032 2.32 1.08 5.01 G Gen GT_vs_TT 0.2021.22 0.9 1.65 G MEGA1 Gen GG_vs_TT 0.029 1.57 1.05 2.34 G Gen GT_vs_TT0.93 1.01 0.86 1.18 G hCV25752810 IDN1 (rs470755

MEGA1 add C_vs_A 0.011 1.49 1.09 2.04 C LETS add C_vs_A 0.03 2.01 1.073.76 C LETS Gen CA_vs_AA 0.047 2.11 1.01 4.4 C Gen CC_vs_AA 0.32 3.160.33 30.5 C MEGA1 Gen CA_vs_AA 0.03 1.49 1.04 2.12 C Gen CC_vs_AA 0.1872.29 0.67 7.84 C hCV16170613 MET (rs2237712 MEGA1 add G_vs_A 0.017 1.381.06 1.8 G LETS add G_vs_A 0.031 1.68 1.05 2.7 G LETS Gen GA_vs_AA 0.1551.45 0.87 2.43 G Gen GG_vs_AA 0.974 2E+06 0 Inf G MEGA1 Gen GA_vs_AA0.033 1.35 1.02 1.77 G Gen GG_vs_AA 0.242 3.86 0.4 37.1 G hCV11726971

FIA (rs2065841 LETS Gen GG_vs_AA 0.016 2.55 1.19 5.45 G MEGA1 GenGA_vs_AA 0.038 1.18 1.01 1.37 G LETS Gen GA_vs_AA 0.242 1.19 0.89 1.61 GGen GG_vs_AA 0.016 2.55 1.19 5.45 G MEGA1 Gen GA_vs_AA 0.038 1.18 1.011.37 G Gen GG_vs_AA 0.591 0.9 0.63 1.3 G hCV30747430 R1I2 (rs1171221MEGA1 add T_vs_C 0.007 1.19 1.05 1.34 T LETS add T_vs_C 0.014 1.35 1.061.71 T LETS Gen TC_vs_CC 0.277 1.18 0.87 1.59 T Gen TT_vs_CC 0.009 2.631.28 5.42 T MEGA1 Gen TC_vs_CC 0.146 1.12 0.96 1.31 T Gen TT_vs_CC 0.0061.61 1.14 2.27 T hCV263841 R1I2 (rs152312 LETS add C_vs_A 1E−04 1.441.19 1.73 C MEGA1 add C_vs_A 0.008 1.15 1.04 1.27 C LETS Gen CA_vs_AA0.13 1.25 0.94 1.66 C Gen CC_vs_AA 7E−05 2.24 1.51 3.34 C MEGA1 GenCA_vs_AA 0.15 1.12 0.96 1.31 C Gen CC_vs_AA 0.007 1.33 1.08 1.65 ChCV4041 NR3C1 (rs6190) MEGA1 dom TT + TC_vs_CC 0.021 1.41 1.05 1.89 TLETS dom TT + TC_vs_CC 0.05 1.65 1 2.73 T LETS Gen TC_vs_CC 0.047 1.681.01 2.79 T Gen TT_vs_CC 0.966 1.06 0.07 17 T MEGA1 Gen TC_vs_CC 0.0381.37 1.02 1.84 T Gen TT_vs_CC 0.139 5.24 0.58 46.9 T hCV2915511

BSL1 (rs62753

LETS Gen CT_vs_TT 0.015 1.95 1.14 3.35 C MEGA1 Gen CC_vs_TT 0.024 3.281.17 9.23 C LETS Gen CC_vs_TT 0.311 3.23 0.33 31.1 C Gen CT_vs_TT 0.0151.95 1.14 3.35 C MEGA1 Gen CC_vs_TT 0.024 3.28 1.17 9.23 C Gen CT_vs_TT0.564 0.92 0.7 1.22 C hCV16177220

DZ1 (rs226691

MEGA1 add C_vs_T 3E−04 1.22 1.09 1.36 C LETS add C_vs_T 0.017 1.28 1.051.57 C LETS Gen CC_vs_TT 0.03 1.65 1.05 2.6 C Gen CT_vs_TT 0.321 1.310.77 2.22 C MEGA1 Gen CC_vs_TT 0.001 1.46 1.16 1.85 C Gen CT_vs_TT 0.2531.18 0.89 1.56 C hCV7584272 R1B1 (rs153692 LETS Gen AG_vs_GG 0.065 1.290.98 1.7 A MEGA1 dom AA + AG_vs_GG 0.044 1.16 1 1.33 A LETS Gen AA_vs_GG0.461 1.24 0.7 2.23 A Gen AG_vs_GG 0.065 1.29 0.98 1.7 A MEGA1 GenAA_vs_GG 0.344 1.16 0.85 1.58 A Gen AG_vs_GG 0.054 1.16 1 1.34 AhCV9327878 R7G1 (rs221765 MEGA1 add G_vs_C 0.006 1.16 1.04 1.29 G LETSadd G_vs_C 0.033 1.24 1.02 1.5 G LETS Gen GC_vs_CC 0.209 1.2 0.9 1.59 GGen GG_vs_CC 0.04 1.57 1.02 2.42 G MEGA1 Gen GC_vs_CC 0.055 1.16 1 1.35G Gen GG_vs_CC 0.012 1.34 1.07 1.69 G hCV15990789 TOG (rs235546 MEGA1rec GG_vs_GA + AA 0.008 1.22 1.05 1.41 G LETS rec GG_vs_GA + AA 0.0131.43 1.08 1.89 G LETS Gen GA_vs_AA 0.602 0.91 0.63 1.31 G Gen GG_vs_AA0.153 1.33 0.9 1.96 G MEGA1 Gen GA_vs_AA 0.256 0.89 0.72 1.09 G GenGG_vs_AA 0.308 1.12 0.9 1.38 G hCV8361354 ANX1 (rs113880 LETS GenCC_vs_AA 0.01 1.75 1.15 2.67 C MEGA1 Gen CA_vs_AA 0.038 0.8 0.64 0.99 CLETS Gen CA_vs_AA 0.179 1.33 0.88 2.01 C Gen CC_vs_AA 0.01 1.75 1.152.67 C MEGA1 Gen CA_vs_AA 0.038 0.8 0.64 0.99 C Gen CC_vs_AA 0.455 0.920.74 1.15 C hCV30500334 ACTR3 (rs61286 LETS add G_vs_A 0.006 1.31 1.081.59 G MEGA1 add G_vs_A 0.017 1.13 1.02 1.25 G LETS Gen GA_vs_AA 0.7581.06 0.72 1.57 G Gen GG_vs_AA 0.024 1.59 1.06 2.38 G MEGA1 Gen GA_vs_AA0.128 1.18 0.95 1.46 G Gen GG_vs_AA 0.017 1.3 1.05 1.62 G hCV27474984K3R1 (rs375666 MEGA1 add A_vs_G 0.011 1.14 1.03 1.26 A LETS add A_vs_G0.026 1.24 1.03 1.5 A LETS Gen AA_vs_GG 0.025 1.54 1.06 2.25 A GenAG_vs_GG 0.305 1.18 0.86 1.61 A MEGA1 Gen AA_vs_GG 0.029 1.25 1.02 1.53A Gen AG_vs_GG 1E−04 1.38 1.17 1.62 A hCV7625318 EKHG4 (rs38681 LETS GenAG_vs_GG 0.003 1.79 1.22 2.62 A MEGA1 Gen AG_vs_GG 0.035 1.24 1.02 1.51A LETS Gen AA_vs_GG 0.497 0.55 0.1 3.04 A Gen AG_vs_GG 0.003 1.79 1.222.62 A MEGA1 Gen AA_vs_GG 0.878 1.06 0.51 2.21 A Gen AG_vs_GG 0.035 1.241.02 1.51 A hCV8598986

LR1A (rs48322

LETS rec CC_vs_CT + TT 0.023 1.36 1.04 1.76 C MEGA1 rec CC_vs_CT + TT0.05 1.15 1 1.33 C LETS Gen CC_vs_TT 0.019 1.83 1.1 3.04 C Gen CT_vs_TT0.173 1.43 0.85 2.39 C MEGA1 Gen CC_vs_TT 0.478 1.1 0.85 1.42 C GenCT_vs_TT 0.663 0.94 0.72 1.23 C hCV926518 P2R5C (rs7467

LETS Gen GT_vs_TT 0.034 1.45 1.03 2.04 G MEGA1 Gen GT_vs_TT 0.05 1.2 11.44 G LETS Gen GG_vs_TT 0.842 0.87 0.23 3.28 G Gen GT_vs_TT 0.034 1.451.03 2.04 G MEGA1 Gen GG_vs_TT 0.525 0.82 0.44 1.53 G Gen GT_vs_TT 0.051.2 1 1.44 G hCV1841975 ROC (rs179981

LETS Gen TT_vs_AA 0.064 1.43 0.98 2.08 T MEGA1 Gen TT_vs_AA 0.006 1.331.09 1.62 T LETS Gen TA_vs_AA 0.495 1.11 0.82 1.5 T Gen TT_vs_AA 0.0641.43 0.98 2.08 T MEGA1 Gen TA_vs_AA 0.772 1.02 0.87 1.21 T Gen TT_vs_AA0.006 1.33 1.09 1.62 T hCV8957432 RAC2 (rs6572) MEGA1 rec CC_vs_CG + GG0.031 1.21 1.02 1.44 C LETS rec CC_vs_CG + GG 0.043 1.41 1.01 1.96 CLETS Gen CC_vs_GG 0.102 1.38 0.94 2.04 C Gen CG_vs_GG 0.863 0.97 0.711.33 C MEGA1 Gen CC_vs_GG 0.02 1.27 1.04 1.55 C Gen CG_vs_GG 0.363 1.080.92 1.27 C hCV29271569 DH13 (rs162697 LETS add T_vs_C 0.014 1.36 1.061.75 T MEGA1 add T_vs_C 0.031 1.15 1.01 1.32 T LETS Gen TC_vs_CC 0.3221.53 0.66 3.56 T Gen TT_vs_CC 0.089 2.04 0.9 4.66 T MEGA1 Gen TC_vs_CC0.906 0.98 0.65 1.47 T Gen TT_vs_CC 0.445 1.17 0.78 1.75 T hCV8703249DH13 (rs16544 LETS add G_vs_T 0.052 1.28 1 1.64 G MEGA1 add G_vs_T 0.021.17 1.03 1.33 G LETS Gen GG_vs_TT 0.149 1.8 0.81 3.99 G Gen GT_vs_TT0.382 1.44 0.64 3.27 G MEGA1 Gen GG_vs_TT 0.193 1.31 0.87 1.95 G GenGT_vs_TT 0.642 1.1 0.73 1.67 G hCV8717752 DH13 (rs167121 LETS add G_vs_A0.024 1.34 1.04 1.72 G MEGA1 rec GG_vs_GA + AA 0.048 1.17 1 1.36 G LETSGen GA_vs_AA 0.114 2.09 0.84 5.22 G Gen GG_vs_AA 0.038 2.58 1.06 6.32 GMEGA1 Gen GA_vs_AA 0.9 1.03 0.66 1.61 G Gen GG_vs_AA 0.414 1.2 0.78 1.85G hCV11975296 SELP (rs6131) MEGA1 add T_vs_C 0.003 1.2 1.06 1.36 T LETSadd T_vs_C 0.025 1.29 1.03 1.62 T LETS Gen TC_vs_CC 0.049 1.34 1 1.8 TGen TT_vs_CC 0.157 1.54 0.85 2.81 T MEGA1 Gen TC_vs_CC 0.004 1.25 1.071.46 T Gen TT_vs_CC 0.148 1.3 0.91 1.86 T hCV9596963 ERPINA5 (rs611 LETSdom AA + AG_vs_GG 0.03 1.61 1.05 2.48 A MEGA1 dom AA + AG_vs_GG 0.0381.27 1.01 1.6 A LETS Gen AA_vs_GG 0.033 1.65 1.04 2.6 A Gen AG_vs_GG0.043 1.59 1.01 2.48 A MEGA1 Gen AA_vs_GG 0.05 1.27 1 1.61 A GenAG_vs_GG 0.047 1.27 1 1.62 A hCV16180170 RPINC1 (rs2227

MEGA1 add T_vs_C 0.01 1.24 1.05 1.47 T LETS add T_vs_C 0.026 1.42 1.041.94 T LETS Gen TC_vs_CC 0.031 1.46 1.04 2.06 T Gen TT_vs_CC 0.442 1.650.46 5.89 T MEGA1 Gen TC_vs_CC 0.052 1.2 1 1.45 T Gen TT_vs_CC 0.0521.93 1 3.73 T hCV1650632 ERPINC1 (rs587 MEGA1 Gen CC_vs_TT 0.005 1.381.1 1.74 C LETS Gen CT_vs_TT 0.026 1.38 1.04 1.83 C LETS Gen CC_vs_TT0.92 1.02 0.66 1.57 C Gen CT_vs_TT 0.026 1.38 1.04 1.83 C MEGA1 GenCC_vs_TT 0.005 1.38 1.1 1.74 C Gen CT_vs_TT 0.191 1r.11 0.95 1.29 ChCV3216426 RS2IP (rs73157 LETS dom AA + AT_vs_TT 0.016 1.47 1.07 2.02 AMEGA1 dom AA + AT_vs_TT 0.02 1.22 1.03 1.44 A LETS Gen AA_vs_TT 0.0161.58 1.09 2.29 A Gen AT_vs_TT 0.043 1.41 1.01 1.98 A MEGA1 Gen AA_vs_TT0.066 1.2 0.99 1.47 A Gen AT_vs_TT 0.023 1.23 1.03 1.47 A hCV25602230IRT6 (rs724623 MEGA1 add G_vs_T 0.008 1.73 1.15 2.58 G LETS add G_vs_T0.012 3.45 1.31 9.07 G LETS Gen GG_vs_TT 0.971 819571

89035 Inf G Gen GT_vs_TT 0.027 3.16 1.14 8.76 G MEGA1 Gen GG_vs_TT 0.1435.14 0.57 46 G Gen GT_vs_TT 0.028 1.64 1.05 2.55 G hCV2086329

ARC (rs495848 MEGA1 rec GG_vs_GA + AA 0.001 1.35 1.13 1.62 G LETS recGG_vs_GA + AA 0.013 1.52 1.09 2.12 G LETS Gen GA_vs_AA 0.943 1.01 0.751.36 G Gen GG_vs_AA 0.026 1.53 1.05 2.23 G MEGA1 Gen GA_vs_AA 0.146 0.890.76 1.04 G Gen GG_vs_AA 0.026 1.26 1.03 1.54 G hCV11466393 TACR1(rs881) LETS add C_vs_G 0.012 1.38 1.07 1.77 C MEGA1 add C_vs_G 0.0371.15 1.01 1.32 C LETS Gen CC_vs_GG 0.121 1.88 0.85 4.17 C Gen CG_vs_GG0.465 1.36 0.6 3.08 C MEGA1 Gen CC_vs_GG 0.185 1.35 0.86 2.12 C GenCG_vs_GG 0.487 1.18 0.74 1.87 C hCV3216649 AF1B (rs105456 LETS dom AA +AG_vs_GG 0.059 1.29 0.99 1.68 A MEGA1 dom AA + AG_vs_GG 0.044 1.16 11.33 A LETS Gen AA_vs_GG 0.336 1.24 0.8 1.93 A Gen AG_vs_GG 0.064 1.30.98 1.72 A MEGA1 Gen AA_vs_GG 0.267 1.14 0.9 1.44 A Gen AG_vs_GG 0.0511.16 1 1.35 A hCV470708 IBS2 (rs109454

LETS add T_vs_G 0.031 1.25 1.02 1.52 T MEGA1 Gen TT_vs_GG 0.041 1.291.01 1.65 T LETS Gen TG_vs_GG 0.108 1.26 0.95 1.66 T Gen TT_vs_GG 0.0671.54 0.97 2.45 T MEGA1 Gen TG_vs_GG 0.755 1.02 0.88 1.19 T Gen TT_vs_GG0.041 1.29 1.01 1.65 T hCV3272537 IAM1 (rs497689 LETS dom AA + AT_vs_TT0.078 1.29 0.97 1.71 A MEGA1 dom AA + AT_vs_TT 0.003 1.26 1.08 1.46 ALETS Gen AA_vs_TT 0.106 1.36 0.94 1.96 A Gen AT_vs_TT 0.132 1.26 0.931.71 A MEGA1 Gen AA_vs_TT 0.113 1.18 0.96 1.44 A Gen AT_vs_TT 0.002 1.291.1 1.52 A hCV27833944 IFSF4 (rs67023

LETS add C_vs_T 0.061 1.35 0.99 1.85 C MEGA1 add C_vs_T 0.009 1.24 1.061.46 C LETS Gen CC_vs_TT 0.423 1.8 0.43 7.59 C Gen CT_vs_TT 0.084 1.350.96 1.91 C MEGA1 Gen CC_vs_TT 0.025 2.06 1.09 3.87 C Gen CT_vs_TT 0.0721.19 0.98 1.43 C hCV1723643 MODL1 (rs22013 LETS rec AA_vs_AC + CC 0.0561.3 0.99 1.7 A MEGA1 rec AA_vs_AC + CC 0.019 1.19 1.03 1.38 A LETS GenAA_vs_CC 0.481 1.26 0.67 2.38 A Gen AC_vs_CC 0.912 0.96 0.5 1.85 A MEGA1Gen AA_vs_CC 0.075 1.36 0.97 1.9 A Gen AC_vs_CC 0.396 1.16 0.82 1.65 AhCV7581501 SP45 (rs132371 LETS Gen CG_vs_GG 0.016 1.51 1.08 2.11 C MEGA1Gen CC_vs_GG 0.034 1.94 1.05 3.6 C LETS Gen CC_vs_GG 0.481 1.43 0.533.89 C Gen CG_vs_GG 0.016 1.51 1.08 2.11 C MEGA1 Gen CC_vs_GG 0.034 1.941.05 3.6 C Gen CG_vs_GG 0.949 0.99 0.84 1.18 C hCV15949414

YLB (rs223462

MEGA1 rec GG_vs_GA + AA 0.003 1.48 1.14 1.92 G LETS rec GG_vs_GA + AA0.036 1.64 1.03 2.61 G LETS Gen GA_vs_AA 0.968 0 #### #### G GenGG_vs_AA 0.969 0 #### #### G MEGA1 Gen GA_vs_AA 0.04 0.1 0.01 0.9 G GenGG_vs_AA 0.095 0.16 0.02 1.38 G hCV356522 TB41 (rs107322 LETS dom TT +TC_vs_CC 0.055 1.41 0.99 2 T MEGA1 dom TT + TC_vs_CC 0.007 1.28 1.071.52 T LETS Gen TC_vs_CC 0.07 1.39 0.97 2 T Gen TT_vs_CC 0.454 1.63 0.465.81 T MEGA1 Gen TC_vs_CC 0.014 1.26 1.05 1.51 T Gen TT_vs_CC 0.174 1.540.83 2.85 T hCV25596789 JF544 (rs651013 LETS add G_vs_C 0.004 2.54 1.344.83 G MEGA1 add G_vs_C 0.01 1.55 1.11 2.18 G LETS Gen GC_vs_CC 0.0112.38 1.22 4.65 G Gen GG_vs_CC 0.971 832450

51533 Inf G MEGA1 Gen GC_vs_CC 0.015 1.52 1.08 2.14 G Gen GG_vs_CC 0.952135256 0 #### G hCV25951992

INT (rs110053

MEGA1 dom AA + AC_vs_CC 0.001 2.11 1.34 3.32 A LETS dom AA + AC_vs_CC0.03 2.32 1.09 4.96 A LETS Gen AA_vs_CC 0.969 0 #### #### A Gen AC_vs_CC0.018 2.58 1.17 5.66 A MEGA1 Gen AA_vs_CC 0.09 6.41 0.75 55 A GenAC_vs_CC 0.004 1.97 1.23 3.13 A CONTROL Non Allele cnt Risk (CONTROLCASE cnt (CONTROL marker annot Endpoint Model Allele frq Genot (CASE frqfrq) Genot2 hCV505733 (rs11126416) LETS Gen G A (0.3642 A A 71 (0.1603)54 (0.1192) A G MEGA1 Gen G A (0.3489 A A 210 (0.1514) 213 (0.1212) A GLETS Gen G A (0.3642 A A 71 (0.1603) 54 (0.1192) A G Gen G A (0.3642 A A71 (0.1603) 54 (0.1192) A G MEGA1 Gen G A (0.3489 A A 210 (0.1514) 213(0.1212) A G Gen G A (0.3489 A A 210 (0.1514) 213 (0.1212) A GhCV2879752 (rs1244565) LETS add A G (0.4658 G G 115 (0.2608) 104(0.2296) G A MEGA1 add A G (0.4692 G G 341 (0.2498) 379 (0.2163) G ALETS Gen A G (0.4658 G G 115 (0.2608) 104 (0.2296) G A Gen A G (0.4658 GG 115 (0.2608) 104 (0.2296) G A MEGA1 Gen A G (0.4692 G G 341 (0.2498)379 (0.2163) G A Gen A G (0.4692 G G 341 (0.2498) 379 (0.2163) G AhCV11503470 (rs1800788) MEGA1 add C T (0.2163 T T 85 (0.0613) 107(0.0611) T C LETS add C T (0.1969 T T 31 (0.07) 17 (0.0376) T C LETS GenC T (0.1969 T T 31 (0.07) 17 (0.0376) T C Gen C T (0.1969 T T 31 (0.07)17 (0.0376) T C MEGA1 Gen C T (0.2163 T T 85 (0.0613) 107 (0.0611) T CGen C T (0.2163 T T 85 (0.0613) 107 (0.0611) T C hCV15860433 (rs2070006)MEGA1 add C T (0.4067 T T 296 (0.2129) 297 (0.1694) T C LETS add C T(0.4011 T T 95 (0.2154) 72 (0.16) T C LETS Gen C T (0.4011 T T 95(0.2154) 72 (0.16) T C Gen C T (0.4011 T T 95 (0.2154) 72 (0.16) T CMEGA1 Gen C T (0.4067 T T 296 (0.2129) 297 (0.1694) T C Gen C T (0.4067T T 296 (0.2129) 297 (0.1694) T C hCV2744023 (rs369328) LETS add G A(0.4491 A A 116 (0.2619) 87 (0.1925) A G MEGA1 add G A (0.4784 A A 370(0.265) 404 (0.2301) A G LETS Gen G A (0.4491 A A 116 (0.2619) 87(0.1925) A G Gen G A (0.4491 A A 116 (0.2619) 87 (0.1925) A G MEGA1 GenG A (0.4784 A A 370 (0.265) 404 (0.2301) A G Gen G A (0.4784 A A 370(0.265) 404 (0.2301) A G hCV27477533 (rs3756008) MEGA1 add A T (0.4064 TT 307 (0.2201) 296 (0.1689) T A LETS add A T (0.4159 T T 101 (0.2285) 88(0.1947) T A LETS Gen A T (0.4159 T T 101 (0.2285) 88 (0.1947) T A Gen AT (0.4159 T T 101 (0.2285) 88 (0.1947) T A MEGA1 Gen A T (0.4064 T T 307(0.2201) 296 (0.1689) T A Gen A T (0.4064 T T 307 (0.2201) 296 (0.1689)T A hCV949676 (rs480802) MEGA1 Gen T C (0.2049 C C 83 (0.0615) 77(0.0443) C T LETS Gen T C (0.1914 C C 29 (0.0662) 17 (0.0376) C T LETSGen T C (0.1914 C C 29 (0.0662) 17 (0.0376) C T Gen T C (0.1914 C C 29(0.0662) 17 (0.0376) C T MEGA1 Gen T C (0.2049 C C 83 (0.0615) 77(0.0443) C T Gen T C (0.2049 C C 83 (0.0615) 77 (0.0443) C T hCV27904396(rs4829996) LETS rec A A (0.2969 A A 64 (0.1448) 79 (0.1744) A G MEGA1Gen A A (0.2903 A A 231 (0.1662) 335 (0.1914) A G LETS Gen A A (0.2969 AA 64 (0.1448) 79 (0.1744) A G Gen A A (0.2969 A A 64 (0.1448) 79(0.1744) A G MEGA1 Gen A A (0.2903 A A 231 (0.1662) 335 (0.1914) A G GenA A (0.2903 A A 231 (0.1662) 335 (0.1914) A G hCV837462 (rs528088) LETSGen A C (0.0796 C C 8 (0.0181) 2 (0.0044) C A MEGA1 dom C C (0.0785 C C5 (0.0036) 19 (0.0109) C A LETS Gen A C (0.0796 C C 8 (0.0181) 2(0.0044) C A Gen A C (0.0796 C C 8 (0.0181) 2 (0.0044) C A MEGA1 Gen C C(0.0785 C C 5 (0.0036) 19 (0.0109) C A Gen C C (0.0785 C C 5 (0.0036) 19(0.0109) C A hCV30440155 (rs6699146) LETS add G C (0.4148 C C 100(0.2278) 84 (0.1858) C G MEGA1 add G C (0.4445 C C 321 (0.2394) 344(0.1969) C G LETS Gen G C (0.4148 C C 100 (0.2278) 84 (0.1858) C G Gen GC (0.4148 C C 100 (0.2278) 84 (0.1858) C G MEGA1 Gen G C (0.4445 C C 321(0.2394) 344 (0.1969) C G Gen G C (0.4445 C C 321 (0.2394) 344 (0.1969)C G hCV28960679 (rs6844764) LETS rec C C (0.4403 C C 74 (0.1674) 82(0.1814) C G MEGA1 dom C C (0.4389 C C 233 (0.1676) 358 (0.2054) C GLETS Gen C C (0.4403 C C 74 (0.1674) 82 (0.1814) C G Gen C C (0.4403 C C74 (0.1674) 82 (0.1814) C G MEGA1 Gen C C (0.4389 C C 233 (0.1676) 358(0.2054) C G Gen C C (0.4389 C C 233 (0.1676) 358 (0.2054) C GhCV1952126 (rs7223784) LETS add C C (0.3031 C C 31 (0.07) 43 (0.0951) CA MEGA1 add C C (0.2801 C C 91 (0.0658) 147 (0.0839) C A LETS Gen C C(0.3031 C C 31 (0.07) 43 (0.0951) C A Gen C C (0.3031 C C 31 (0.07) 43(0.0951) C A MEGA1 Gen C C (0.2801 C C 91 (0.0658) 147 (0.0839) C A GenC C (0.2801 C C 91 (0.0658) 147 (0.0839) C A hCV31749285 (rs8178591)LETS rec T T (0.2914 T T 40 (0.0903) 32 (0.0706) T C MEGA1 rec T T(0.2781 T T 86 (0.0618) 126 (0.072) T C LETS Gen T T (0.2914 T T 40(0.0903) 32 (0.0706) T C Gen T T (0.2914 T T 40 (0.0903) 32 (0.0706) T CMEGA1 Gen T T (0.2781 T T 86 (0.0618) 126 (0.072) T C Gen T T (0.2781 TT 86 (0.0618) 126 (0.072) T C hCV3187716 AGTR1 (rs5186

LETS dom A C (0.2931 C C 44 (0.1005) 39 (0.0872) C A MEGA1 add C C(0.3088 C C 102 (0.0759) 165 (0.0942) C A LETS Gen C C (0.2931 C C 44(0.1005) 39 (0.0872) C A Gen C C (0.2931 C C 44 (0.1005) 39 (0.0872) C AMEGA1 Gen C C (0.3088 C C 102 (0.0759) 165 (0.0942) C A Gen C C (0.3088C C 102 (0.0759) 165 (0.0942) C A hCV9493081

KT3 (rs105830

LETS add C T (0.2639 T T 50 (0.1131) 32 (0.071) T C MEGA1 add C T (0.286T T 152 (0.1126) 128 (0.0729) T C LETS Gen C T (0.2639 T T 50 (0.1131)32 (0.071) T C Gen C T (0.2639 T T 50 (0.1131) 32 (0.071) T C MEGA1 GenC T (0.286 T T 152 (0.1126) 128 (0.0729) T C Gen C T (0.286 T T 152(0.1126) 128 (0.0729) T C hCV30690780

T3 (rs1073788 LETS add A C (0.204 C C 39 (0.0888) 21 (0.0466) C A MEGA1add A C (0.2294 C C 114 (0.0845) 89 (0.051) C A LETS Gen A C (0.204 C C39 (0.0888) 21 (0.0466) C A Gen A C (0.204 C C 39 (0.0888) 21 (0.0466) CA MEGA1 Gen A C (0.2294 C C 114 (0.0845) 89 (0.051) C A Gen A C (0.2294C C 114 (0.0845) 89 (0.051) C A hCV31523557

T3 (rs1075480 LETS add G A (0.1667 A A 24 (0.0544) 15 (0.0333) A G MEGA1add G A (0.1935 A A 74 (0.0548) 74 (0.0421) A G LETS Gen G A (0.1667 A A24 (0.0544) 15 (0.0333) A G Gen G A (0.1667 A A 24 (0.0544) 15 (0.0333)A G MEGA1 Gen G A (0.1935 A A 74 (0.0548) 74 (0.0421) A G Gen G A(0.1935 A A 74 (0.0548) 74 (0.0421) A G hCV26719108

T3 (rs1092703 LETS add T C (0.3319 C C 70 (0.1584) 49 (0.1084) C T MEGA1add T C (0.3579 C C 222 (0.1649) 225 (0.1292) C T LETS Gen T C (0.3319 CC 70 (0.1584) 49 (0.1084) C T Gen T C (0.3319 C C 70 (0.1584) 49(0.1084) C T MEGA1 Gen T C (0.3579 C C 222 (0.1649) 225 (0.1292) C T GenT C (0.3579 C C 222 (0.1649) 225 (0.1292) C T hCV26719121

T3 (rs1092704 LETS add T C (0.167 C C 25 (0.0566) 15 (0.0332) C T MEGA1add T C (0.1929 C C 72 (0.0534) 73 (0.0416) C T LETS Gen T C (0.167 C C25 (0.0566) 15 (0.0332) C T Gen T C (0.167 C C 25 (0.0566) 15 (0.0332) CT MEGA1 Gen T C (0.1929 C C 72 (0.0534) 73 (0.0416) C T Gen T C (0.1929C C 72 (0.0534) 73 (0.0416) C T hCV26719227

T3 (rs1092706 LETS add C A (0.147 A A 12 (0.0271) 10 (0.0223) A C MEGA1add C A (0.1654 A A 52 (0.0385) 51 (0.0291) A C LETS Gen C A (0.147 A A12 (0.0271) 10 (0.0223) A C Gen C A (0.147 A A 12 (0.0271) 10 (0.0223) AC MEGA1 Gen C A (0.1654 A A 52 (0.0385) 51 (0.0291) A C Gen C A (0.1654A A 52 (0.0385) 51 (0.0291) A C hCV31523638

T3 (rs1203701 LETS add G A (0.1294 A A 12 (0.0273) 9 (0.0199) A G MEGA1add G A (0.1502 A A 40 (0.0296) 36 (0.0205) A G LETS Gen G A (0.1294 A A12 (0.0273) 9 (0.0199) A G Gen G A (0.1294 A A 12 (0.0273) 9 (0.0199) AG MEGA1 Gen G A (0.1502 A A 40 (0.0296) 36 (0.0205) A G Gen G A (0.1502A A 40 (0.0296) 36 (0.0205) A G hCV30690777

T3 (rs1204558 MEGA1 add G A (0.1439 A A 36 (0.0267) 27 (0.0154) A G LETSadd G A (0.1396 A A 11 (0.0253) 8 (0.018) A G LETS Gen G A (0.1396 A A11 (0.0253) 8 (0.018) A G Gen G A (0.1396 A A 11 (0.0253) 8 (0.018) A GMEGA1 Gen G A (0.1439 A A 36 (0.0267) 27 (0.0154) A G Gen G A (0.1439 AA 36 (0.0267) 27 (0.0154) A G hCV31523650

T3 (rs1204893 LETS add C T (0.18 T T 25 (0.0571) 16 (0.0356) T C MEGA1add C T (0.2011 T T 74 (0.0536) 82 (0.0468) T C LETS Gen C T (0.18 T T25 (0.0571) 16 (0.0356) T C Gen C T (0.18 T T 25 (0.0571) 16 (0.0356) TC MEGA1 Gen C T (0.2011 T T 74 (0.0536) 82 (0.0468) T C Gen C T (0.2011T T 74 (0.0536) 82 (0.0468) T C hCV30690778

T3 (rs1214041 LETS add T C (0.1718 C C 19 (0.0433) 15 (0.0333) C T MEGA1add T C (0.1872 C C 59 (0.0437) 52 (0.0296) C T LETS Gen T C (0.1718 C C19 (0.0433) 15 (0.0333) C T Gen T C (0.1718 C C 19 (0.0433) 15 (0.0333)C T MEGA1 Gen T C (0.1872 C C 59 (0.0437) 52 (0.0296) C T Gen T C(0.1872 C C 59 (0.0437) 52 (0.0296) C T hCV31523608

T3 (rs1274429 MEGA1 add A G (0.3236 G G 186 (0.138) 197 (0.1124) G ALETS add A G (0.296 G G 57 (0.1293) 43 (0.0953) G A LETS Gen A G (0.296G G 57 (0.1293) 43 (0.0953) G A Gen A G (0.296 G G 57 (0.1293) 43(0.0953) G A MEGA1 Gen A G (0.3236 G G 186 (0.138) 197 (0.1124) G A GenA G (0.3236 G G 186 (0.138) 197 (0.1124) G A hCV233148

T3 (rs141712

LETS add G C (0.2627 C C 50 (0.1129) 32 (0.0706) C G MEGA1 add G C(0.2854 C C 163 (0.1174) 129 (0.0734) C G LETS Gen G C (0.2627 C C 50(0.1129) 32 (0.0706) C G Gen G C (0.2627 C C 50 (0.1129) 32 (0.0706) C GMEGA1 Gen G C (0.2854 C C 163 (0.1174) 129 (0.0734) C G Gen G C (0.2854C C 163 (0.1174) 129 (0.0734) C G hCV12073840 AKT3 (rs14403) LETS Gen CT (0.2228 T T 29 (0.0664) 24 (0.0532) T C MEGA1 Gen C T (0.2392 T T 90(0.0668) 85 (0.0484) T C LETS Gen C T (0.2228 T T 29 (0.0664) 24(0.0532) T C Gen C T (0.2228 T T 29 (0.0664) 24 (0.0532) T C MEGA1 Gen CT (0.2392 T T 90 (0.0668) 85 (0.0484) T C Gen C T (0.2392 T T 90(0.0668) 85 (0.0484) T C hCV1678674

KT3 (rs1458023 LETS add T C (0.1808 C C 31 (0.0711) 18 (0.0402) C TMEGA1 add T C (0.2008 C C 80 (0.0593) 82 (0.0468) C T LETS Gen T C(0.1808 C C 31 (0.0711) 18 (0.0402) C T Gen T C (0.1808 C C 31 (0.0711)18 (0.0402) C T MEGA1 Gen T C (0.2008 C C 80 (0.0593) 82 (0.0468) C TGen T C (0.2008 C C 80 (0.0593) 82 (0.0468) C T hCV97631

KT3 (rs1538773 LETS add T G (0.2051 G G 35 (0.0794) 21 (0.0466) G TMEGA1 add T G (0.2279 G G 102 (0.0756) 89 (0.0508) G T LETS Gen T G(0.2051 G G 35 (0.0794) 21 (0.0466) G T Gen T G (0.2051 G G 35 (0.0794)21 (0.0466) G T MEGA1 Gen T G (0.2279 G G 102 (0.0756) 89 (0.0508) G TGen T G (0.2279 G G 102 (0.0756) 89 (0.0508) G T hCV8688111

KT3 (rs1578275 LETS add G C (0.167 C C 20 (0.0459) 12 (0.0269) C G MEGA1add G C (0.1846 C C 58 (0.0432) 52 (0.0298) C G LETS Gen G C (0.167 C C20 (0.0459) 12 (0.0269) C G Gen G C (0.167 C C 20 (0.0459) 12 (0.0269) CG MEGA1 Gen G C (0.1846 C C 58 (0.0432) 52 (0.0298) C G Gen G C (0.1846C C 58 (0.0432) 52 (0.0298) C G hCV15885425

KT3 (rs229075

LETS add A C (0.1726 C C 27 (0.0615) 15 (0.0332) C A MEGA1 add A C(0.199 C C 76 (0.0564) 85 (0.0485) C A LETS Gen A C (0.1726 C C 27(0.0615) 15 (0.0332) C A Gen A C (0.1726 C C 27 (0.0615) 15 (0.0332) C AMEGA1 Gen A C (0.199 C C 76 (0.0564) 85 (0.0485) C A Gen A C (0.199 C C76 (0.0564) 85 (0.0485) C A hCV1678682 AKT3 (rs320339 LETS add G T(0.1752 T T 30 (0.0683) 18 (0.0402) T G MEGA1 add G T (0.1945 T T 84(0.0624) 75 (0.0428) T G LETS Gen G T (0.1752 T T 30 (0.0683) 18(0.0402) T G Gen G T (0.1752 T T 30 (0.0683) 18 (0.0402) T G MEGA1 Gen GT (0.1945 T T 84 (0.0624) 75 (0.0428) T G Gen G T (0.1945 T T 84(0.0624) 75 (0.0428) T G hCV29210363

KT3 (rs6656918 LETS add A G (0.2062 G G 38 (0.0868) 22 (0.0488) G AMEGA1 add A G (0.2303 G G 111 (0.0823) 91 (0.0519) G A LETS Gen A G(0.2062 G G 38 (0.0868) 22 (0.0488) G A Gen A G (0.2062 G G 38 (0.0868)22 (0.0488) G A MEGA1 Gen A G (0.2303 G G 111 (0.0823) 91 (0.0519) G AGen A G (0.2303 G G 111 (0.0823) 91 (0.0519) G A hCV31523643

KT3 (rs6671475 LETS add A G (0.1737 G G 27 (0.0611) 15 (0.0332) G AMEGA1 add A G (0.198 G G 76 (0.0563) 80 (0.0457) G A LETS Gen A G(0.1737 G G 27 (0.0611) 15 (0.0332) G A Gen A G (0.1737 G G 27 (0.0611)15 (0.0332) G A MEGA1 Gen A G (0.198 G G 76 (0.0563) 80 (0.0457) G A GenA G (0.198 G G 76 (0.0563) 80 (0.0457) G A hCV26719113

KT3 (rs751734

LETS add C T (0.1602 T T 24 (0.0557) 16 (0.0364) T C MEGA1 add C T(0.1871 T T 78 (0.058) 67 (0.0384) T C LETS Gen C T (0.1602 T T 24(0.0557) 16 (0.0364) T C Gen C T (0.1602 T T 24 (0.0557) 16 (0.0364) T CMEGA1 Gen C T (0.1871 T T 78 (0.058) 67 (0.0384) T C Gen C T (0.1871 T T78 (0.058) 67 (0.0384) T C hCV26034142

KT3 (rs9428576 LETS add T C (0.4347 C C 112 (0.2534) 96 (0.2124) C TMEGA1 rec T C (0.4504 C C 318 (0.2359) 346 (0.1974) C T LETS Gen T C(0.4347 C C 112 (0.2534) 96 (0.2124) C T Gen T C (0.4347 C C 112(0.2534) 96 (0.2124) C T MEGA1 Gen T C (0.4504 C C 318 (0.2359) 346(0.1974) C T Gen T C (0.4504 C C 318 (0.2359) 346 (0.1974) C ThCV2303891 POH (rs180169

MEGA1 add G G (0.0555 G G 4 (0.0029) 3 (0.0017) G C LETS add G G (0.0512G G 0 (0) 1 (0.0022) G C LETS Gen G G (0.0512 G G 0 (0) 1 (0.0022) G CGen G G (0.0512 G G 0 (0) 1 (0.0022) G C MEGA1 Gen G G (0.0555 G G 4(0.0029) 3 (0.0017) G C Gen G G (0.0555 G G 4 (0.0029) 3 (0.0017) G ChCV2456747 orf114 (rs38200 MEGA1 add G A (0.3342 A A 212 (0.152) 215(0.1229) A G LETS add G A (0.2969 A A 55 (0.1244) 44 (0.0971) A G LETSGen G A (0.2969 A A 55 (0.1244) 44 (0.0971) A G Gen G A (0.2969 A A 55(0.1244) 44 (0.0971) A G MEGA1 Gen G A (0.3342 A A 212 (0.152) 215(0.1229) A G Gen G A (0.3342 A A 212 (0.152) 215 (0.1229) A G hCV2403368QTNF6 (rs2295

LETS rec C C (0.2594 C C 25 (0.0566) 26 (0.0574) C G MEGA1 rec C C(0.2484 C C 78 (0.056) 106 (0.0604) C G LETS Gen C C (0.2594 C C 25(0.0566) 26 (0.0574) C G Gen C C (0.2594 C C 25 (0.0566) 26 (0.0574) C GMEGA1 Gen C C (0.2484 C C 78 (0.056) 106 (0.0604) C G Gen C C (0.2484 CC 78 (0.056) 106 (0.0604) C G hCV7574127 orf167 (rs17371 LETS add G G(0.4746 G G 80 (0.181) 97 (0.2141) G A MEGA1 add G G (0.4837 G G 292(0.2108) 424 (0.242) G A LETS Gen G G (0.4746 G G 80 (0.181) 97 (0.2141)G A Gen G G (0.4746 G G 80 (0.181) 97 (0.2141) G A MEGA1 Gen G G (0.4837G G 292 (0.2108) 424 (0.242) G A Gen G G (0.4837 G G 292 (0.2108) 424(0.242) G A hCV25959498 orf46 (rs345186 LETS add A A (0.083 A A 1(0.0023) 6 (0.0133) A G MEGA1 add A A (0.0843 A A 6 (0.0043) 17 (0.0097)A G LETS Gen A A (0.083 A A 1 (0.0023) 6 (0.0133) A G Gen A A (0.083 A A1 (0.0023) 6 (0.0133) A G MEGA1 Gen A A (0.0843 A A 6 (0.0043) 17(0.0097) A G Gen A A (0.0843 A A 6 (0.0043) 17 (0.0097) A G hCV25959466orf46 (rs354955 MEGA1 add C C (0.0854 C C 7 (0.005) 18 (0.0103) C T LETSadd C C (0.0808 C C 1 (0.0023) 5 (0.0111) C T LETS Gen C C (0.0808 C C 1(0.0023) 5 (0.0111) C T Gen C C (0.0808 C C 1 (0.0023) 5 (0.0111) C TMEGA1 Gen C C (0.0854 C C 7 (0.005) 18 (0.0103) C T Gen C C (0.0854 C C7 (0.005) 18 (0.0103) C T hCV25768636

DC36 (rs42791

MEGA1 rec G A (0.3444 A A 188 (0.1356) 194 (0.1105) A G LETS rec G A(0.3271 A A 68 (0.1538) 48 (0.1064) A G LETS Gen G A (0.3271 A A 68(0.1538) 48 (0.1064) A G Gen G A (0.3271 A A 68 (0.1538) 48 (0.1064) A GMEGA1 Gen G A (0.3444 A A 188 (0.1356) 194 (0.1105) A G Gen G A (0.3444A A 188 (0.1356) 194 (0.1105) A G hCV25991132 CCDC41 ( ) MEGA1 rec A A(0.0924 A A 13 (0.0094) 6 (0.0034) A G LETS rec A A (0.0971 A A 1(0.0023) 5 (0.011) A G LETS Gen A A (0.0971 A A 1 (0.0023) 5 (0.011) A GGen A A (0.0971 A A 1 (0.0023) 5 (0.011) A G MEGA1 Gen A A (0.0924 A A13 (0.0094) 6 (0.0034) A G Gen A A (0.0924 A A 13 (0.0094) 6 (0.0034) AG hCV3164397

YA5 (rs100439

LETS rec T T (0.1678 T T 9 (0.0204) 8 (0.0177) T C MEGA1 dom T T (0.1359T T 12 (0.0086) 34 (0.0194) T C LETS Gen T T (0.1678 T T 9 (0.0204) 8(0.0177) T C Gen T T (0.1678 T T 9 (0.0204) 8 (0.0177) T C MEGA1 Gen T T(0.1359 T T 12 (0.0086) 34 (0.0194) T C Gen T T (0.1359 T T 12 (0.0086)34 (0.0194) T C hCV3230083 P4V2 (rs100136 MEGA1 Gen C A (0.4278 A A 282(0.2098) 329 (0.1877) A C LETS Gen C A (0.4533 A A 97 (0.2195) 100(0.2222) A C LETS Gen C A (0.4533 A A 97 (0.2195) 100 (0.2222) A C Gen CA (0.4533 A A 97 (0.2195) 100 (0.2222) A C MEGA1 Gen C A (0.4278 A A 282(0.2098) 329 (0.1877) A C Gen C A (0.4278 A A 282 (0.2098) 329 (0.1877)A C hCV25990131 P4V2 (rs131462 MEGA1 add C C (0.36 C C 149 (0.1067) 229(0.1306) C A LETS add C C (0.3492 C C 32 (0.0726) 63 (0.1397) C A LETSGen C C (0.3492 C C 32 (0.0726) 63 (0.1397) C A Gen C C (0.3492 C C 32(0.0726) 63 (0.1397) C A MEGA1 Gen C C (0.36 C C 149 (0.1067) 229(0.1306) C A Gen C C (0.36 C C 149 (0.1067) 229 (0.1306) C A hCV15968043

P4V2 (rs22924

MEGA1 dom T A (0.4126 A A 292 (0.2108) 300 (0.172) A T LETS dom T A(0.4327 A A 97 (0.219) 92 (0.2031) A T LETS Gen T A (0.4327 A A 97(0.219) 92 (0.2031) A T Gen T A (0.4327 A A 97 (0.219) 92 (0.2031) A TMEGA1 Gen T A (0.4126 A A 292 (0.2108) 300 (0.172) A T Gen T A (0.4126 AA 292 (0.2108) 300 (0.172) A T hCV3230096

P4V2 (rs38171

LETS dom C T (0.4369 T T 95 (0.2149) 92 (0.2035) T C MEGA1 dom C T(0.4164 T T 301 (0.2165) 309 (0.1776) T C LETS Gen C T (0.4369 T T 95(0.2149) 92 (0.2035) T C Gen C T (0.4369 T T 95 (0.2149) 92 (0.2035) T CMEGA1 Gen C T (0.4164 T T 301 (0.2165) 309 (0.1776) T C Gen C T (0.4164T T 301 (0.2165) 309 (0.1776) T C hCV11786147

P4V2 (rs48626

LETS dom G T (0.433 T T 94 (0.2151) 90 (0.2009) T G MEGA1 dom G T(0.4111 T T 278 (0.2065) 303 (0.1731) T G LETS Gen G T (0.433 T T 94(0.2151) 90 (0.2009) T G Gen G T (0.433 T T 94 (0.2151) 90 (0.2009) T GMEGA1 Gen G T (0.4111 T T 278 (0.2065) 303 (0.1731) T G Gen G T (0.4111T T 278 (0.2065) 303 (0.1731) T G hCV3230084

P4V2 (rs76829

MEGA1 Gen C T (0.3945 T T 247 (0.1839) 288 (0.1648) T C LETS Gen C T(0.4257 T T 75 (0.1705) 87 (0.1929) T C LETS Gen C T (0.4257 T T 75(0.1705) 87 (0.1929) T C Gen C T (0.4257 T T 75 (0.1705) 87 (0.1929) T CMEGA1 Gen C T (0.3945 T T 247 (0.1839) 288 (0.1648) T C Gen C T (0.3945T T 247 (0.1839) 288 (0.1648) T C hCV26265231

P4V2 (rs76840

MEGA1 dom G A (0.459 A A 335 (0.2496) 373 (0.2141) A G LETS dom G A(0.4812 A A 116 (0.2619) 116 (0.2561) A G LETS Gen G A (0.4812 A A 116(0.2619) 116 (0.2561) A G Gen G A (0.4812 A A 116 (0.2619) 116 (0.2561)A G MEGA1 Gen G A (0.459 A A 335 (0.2496) 373 (0.2141) A G Gen G A(0.459 A A 335 (0.2496) 373 (0.2141) A G hCV9860072 HX38 (rs105036 LETSGen C A (0.3521 A A 62 (0.14) 62 (0.1369) A C MEGA1 Gen C A (0.354 A A205 (0.1488) 220 (0.1259) A C LETS Gen C A (0.3521 A A 62 (0.14) 62(0.1369) A C Gen C A (0.3521 A A 62 (0.14) 62 (0.1369) A C MEGA1 Gen C A(0.354 A A 205 (0.1488) 220 (0.1259) A C Gen C A (0.354 A A 205 (0.1488)220 (0.1259) A C hCV2103346

564J102 (rs117 LETS rec T C (0.4257 C C 104 (0.2358) 77 (0.1707) C TMEGA1 dom T C (0.4422 C C 301 (0.2231) 359 (0.2046) C T LETS Gen T C(0.4257 C C 104 (0.2358) 77 (0.1707) C T Gen T C (0.4257 C C 104(0.2358) 77 (0.1707) C T MEGA1 Gen T C (0.4422 C C 301 (0.2231) 359(0.2046) C T Gen T C (0.4422 C C 301 (0.2231) 359 (0.2046) C ThCV12086148

564J102 (rs18

LETS rec A A (0.2417 A A 24 (0.0544) 25 (0.0554) A G MEGA1 Gen A A(0.2363 A A 56 (0.0404) 100 (0.0573) A G LETS Gen A A (0.2417 A A 24(0.0544) 25 (0.0554) A G Gen A A (0.2417 A A 24 (0.0544) 25 (0.0554) A GMEGA1 Gen A A (0.2363 A A 56 (0.0404) 100 (0.0573) A G Gen A A (0.2363 AA 56 (0.0404) 100 (0.0573) A G hCV25473516

SP11 (rs22720

LETS Gen C T (0.365 T T 70 (0.1584) 53 (0.1173) T C MEGA1 Gen C T(0.3501 T T 206 (0.1483) 209 (0.1194) T C LETS Gen C T (0.365 T T 70(0.1584) 53 (0.1173) T C Gen C T (0.365 T T 70 (0.1584) 53 (0.1173) T CMEGA1 Gen C T (0.3501 T T 206 (0.1483) 209 (0.1194) T C Gen C T (0.3501T T 206 (0.1483) 209 (0.1194) T C hCV15871021

BF1 (rs207249

LETS rec A A (0.4084 A A 70 (0.1584) 66 (0.1457) A G MEGA1 dom A A(0.3927 A A 168 (0.1206) 269 (0.154) A G LETS Gen A A (0.4084 A A 70(0.1584) 66 (0.1457) A G Gen A A (0.4084 A A 70 (0.1584) 66 (0.1457) A GMEGA1 Gen A A (0.3927 A A 168 (0.1206) 269 (0.154) A G Gen A A (0.3927 AA 168 (0.1206) 269 (0.154) A G hCV491830

S8L2 (rs30875

LETS add C C (0.4601 C C 74 (0.1689) 94 (0.2084) C T MEGA1 add C C(0.4385 C C 236 (0.17) 356 (0.2035) C T LETS Gen C C (0.4601 C C 74(0.1689) 94 (0.2084) C T Gen C C (0.4601 C C 74 (0.1689) 94 (0.2084) C TMEGA1 Gen C C (0.4385 C C 236 (0.17) 356 (0.2035) C T Gen C C (0.4385 CC 236 (0.17) 356 (0.2035) C T hCV2017876

S8L3 (rs38185

LETS add A A (0.4889 A A 96 (0.2167) 113 (0.25) A G MEGA1 add A A(0.4794 A A 282 (0.2049) 394 (0.2254) A G LETS Gen A A (0.4889 A A 96(0.2167) 113 (0.25) A G Gen A A (0.4889 A A 96 (0.2167) 113 (0.25) A GMEGA1 Gen A A (0.4794 A A 282 (0.2049) 394 (0.2254) A G Gen A A (0.4794A A 282 (0.2049) 394 (0.2254) A G hCV12066124 F11 (rs2036914 MEGA1 add TT (0.4786 T T 233 (0.1675) 407 (0.232) T C LETS add T T (0.457 T T 69(0.1558) 99 (0.2185) T C LETS Gen T T (0.457 T T 69 (0.1558) 99 (0.2185)T C Gen T T (0.457 T T 69 (0.1558) 99 (0.2185) T C MEGA1 Gen T T (0.4786T T 233 (0.1675) 407 (0.232) T C Gen T T (0.4786 T T 233 (0.1675) 407(0.232) T C hCV16172935 F11 (rs2241817 LETS rec G G (0.3451 G G 52(0.1176) 46 (0.1018) G A MEGA1 rec G G (0.358 G G 139 (0.1004) 219(0.1259) G A LETS Gen G G (0.3451 G G 52 (0.1176) 46 (0.1018) G A Gen GG (0.3451 G G 52 (0.1176) 46 (0.1018) G A MEGA1 Gen G G (0.358 G G 139(0.1004) 219 (0.1259) G A Gen G G (0.358 G G 139 (0.1004) 219 (0.1259) GA hCV3230038 F11 (rs2289252 LETS add C T (0.4279 T T 107 (0.2426) 93(0.2062) T C MEGA1 add C T (0.4166 T T 314 (0.2331) 309 (0.1766) T CLETS Gen C T (0.4279 T T 107 (0.2426) 93 (0.2062) T C Gen C T (0.4279 TT 107 (0.2426) 93 (0.2062) T C MEGA1 Gen C T (0.4166 T T 314 (0.2331)309 (0.1766) T C Gen C T (0.4166 T T 314 (0.2331) 309 (0.1766) T ChCV27474895 F11 (rs3756011 MEGA1 add C A (0.4182 A A 326 (0.2364) 312(0.1785) A C LETS add C A (0.4248 A A 107 (0.2415) 92 (0.2035) A C LETSGen C A (0.4248 A A 107 (0.2415) 92 (0.2035) A C Gen C A (0.4248 A A 107(0.2415) 92 (0.2035) A C MEGA1 Gen C A (0.4182 A A 326 (0.2364) 312(0.1785) A C Gen C A (0.4182 A A 326 (0.2364) 312 (0.1785) A ChCV25474413 F11 (rs3822057 LETS Gen A A (0.4912 A A 91 (0.2054) 116(0.2561) A C MEGA1 Gen A A (0.51 A A 269 (0.1971) 457 (0.2604) A C LETSGen A A (0.4912 A A 91 (0.2054) 116 (0.2561) A C Gen A A (0.4912 A A 91(0.2054) 116 (0.2561) A C MEGA1 Gen A A (0.51 A A 269 (0.1971) 457(0.2604) A C Gen A A (0.51 A A 269 (0.1971) 457 (0.2604) A C hCV27490984F11 (rs3822058 LETS rec A A (0.3462 A A 54 (0.1222) 46 (0.1018) A GMEGA1 rec A A (0.3589 A A 135 (0.097) 219 (0.1254) A G LETS Gen A A(0.3462 A A 54 (0.1222) 46 (0.1018) A G Gen A A (0.3462 A A 54 (0.1222)46 (0.1018) A G MEGA1 Gen A A (0.3589 A A 135 (0.097) 219 (0.1254) A GGen A A (0.3589 A A 135 (0.097) 219 (0.1254) A G hCV25474414 F11(rs4253399 MEGA1 add T G (0.3872 G G 278 (0.2067) 264 (0.1504) G T LETSadd T G (0.3902 G G 94 (0.2132) 80 (0.1774) G T LETS Gen T G (0.3902 G G94 (0.2132) 80 (0.1774) G G Gen T G (0.3902 G G 94 (0.2132) 80 (0.1774)G T MEGA1 Gen T G (0.3872 G G 278 (0.2067) 264 (0.1504) G T Gen T G(0.3872 G G 278 (0.2067) 264 (0.1504) G T hCV26038139 F11 (rs4253405MEGA1 Gen G G (0.3744 G G 142 (0.102) 249 (0.1421) G A LETS Gen G G(0.3639 G G 63 (0.1429) 52 (0.115) G A LETS Gen G G (0.3639 G G 63(0.1429) 52 (0.115) G A Gen G G (0.3639 G G 63 (0.1429) 52 (0.115) G AMEGA1 Gen G G (0.3744 G G 142 (0.102) 249 (0.1421) G A Gen G G (0.3744 GG 142 (0.102) 249 (0.1421) G A hCV3230119 F11 (rs4253430 LETS rec C C(0.3518 C C 52 (0.1179) 48 (0.1062) C G MEGA1 rec C C (0.3562 C C 135(0.0971) 218 (0.1244) C G LETS Gen C C (0.3518 C C 52 (0.1179) 48(0.1062) C G Gen C C (0.3518 C C 52 (0.1179) 48 (0.1062) C G MEGA1 Gen CC (0.3562 C C 135 (0.0971) 218 (0.1244) C G Gen C C (0.3562 C C 135(0.0971) 218 (0.1244) C G hCV8241630 F11 (rs925451) MEGA1 add G A(0.3886 A A 289 (0.2128) 272 (0.1554) A G LETS add G A (0.4071 A A 95(0.2154) 87 (0.1925) A G LETS Gen G A (0.4071 A A 95 (0.2154) 87(0.1925) A G Gen G A (0.4071 A A 95 (0.2154) 87 (0.1925) A G MEGA1 Gen GA (0.3886 A A 289 (0.2128) 272 (0.1554) A G Gen G A (0.3886 A A 289(0.2128) 272 (0.1554) A G hCV8726802 F2 (rs1799963) MEGA1 add G A(0.0106 A A 0 (0) 0 (0) A G LETS add G A (0.0111 A A 0 (0) 0 (0) A GLETS Gen G G (0.0111 G G 0 (0) 0 (0) G A MEGA1 Gen G A (0.0106 A A 0 (0)0 (0) A G hCV27480803 F5 (rs3766103) MEGA1 add T C (0.4411 C C 346(0.2493) 351 (0.2008) C T LETS add T C (0.4062 C C 96 (0.2177) 73(0.1611) C T LETS Gen T C (0.4062 C C 96 (0.2177) 73 (0.1611) C T Gen TC (0.4062 C C 96 (0.2177) 73 (0.1611) C T MEGA1 Gen T C (0.4411 C C 346(0.2493) 351 (0.2008) C T Gen T C (0.4411 C C 346 (0.2493) 351 (0.2008)C T hCV8919444 F5 (rs4524) MEGA1 add C C (0.2553 C C 76 (0.0548) 107(0.0611) C T LETS add C C (0.2577 C C 24 (0.0542) 32 (0.0708) C T LETSGen C C (0.2577 C C 24 (0.0542) 32 (0.0708) C T Gen C C (0.2577 C C 24(0.0542) 32 (0.0708) C T MEGA1 Gen C C (0.2553 C C 76 (0.0548) 107(0.0611) C T Gen C C (0.2553 C C 76 (0.0548) 107 (0.0611) C T hCV8919442F5 (rs4525) MEGA1 add C C (0.2558 C C 74 (0.0541) 107 (0.0609) C T LETSadd C C (0.2556 C C 25 (0.0568) 31 (0.0689) C T LETS Gen C C (0.2556 C C25 (0.0568) 31 (0.0689) C T Gen C C (0.2556 C C 25 (0.0568) 31 (0.0689)C T MEGA1 Gen C C (0.2558 C C 74 (0.0541) 107 (0.0609) C T Gen C C(0.2558 C C 74 (0.0541) 107 (0.0609) C T hCV8919451 F5 (rs6016) MEGA1add A A (0.255 A A 78 (0.0562) 108 (0.0615) A G LETS add A A (0.2578 A A24 (0.0544) 31 (0.0689) A G LETS Gen A A (0.2578 A A 24 (0.0544) 31(0.0689) A G Gen A A (0.2578 A A 24 (0.0544) 31 (0.0689) A G MEGA1 Gen AA (0.255 A A 78 (0.0562) 108 (0.061S) A G Gen A A (0.255 A A 78 (0.0562)108 (0.0615) A G hCV2288095 F9 (rs378815) LETS Gen T T (0.3711 T T 80(0.1814) 107 (0.2378) T C MEGA1 Gen T T (0.3545 T T 306 (0.2201) 431(0.2464) T C LETS Gen T T (0.3711 T T 80 (0.1814) 107 (0.2378) T C Gen TT (0.3711 T T 80 (0.1814) 107 (0.2378) T C MEGA1 Gen T T (0.3545 T T 306(0.2201) 431 (0.2464) T C Gen T T (0.3545 T T 306 (0.2201) 431 (0.2464)T C hCV596326 F9 (rs398101) LETS rec G G (0.3363 G G 75 (0.1705) 92(0.2035) G A MEGA1 Gen G G (0.3174 G G 257 (0.1857) 381 (0.2175) G ALETS Gen G G (0.3363 G G 75 (0.1705) 92 (0.2035) G A Gen G G (0.3363 G G75 (0.1705) 92 (0.2035) G A MEGA1 Gen G G (0.3174 G G 257 (0.1857) 381(0.2175) G A Gen G G (0.3174 G G 257 (0.1857) 381 (0.2175) G A hCV596330F9 (rs422187) LETS add C C (0.3267 C C 70 (0.1587) 87 (0.1933) C A MEGA1add C C (0.3178 C C 243 (0.176) 376 (0.2147) C A LETS Gen C C (0.3267 CC 70 (0.1587) 87 (0.1933) C A Gen C C (0.3267 C C 70 (0.1587) 87(0.1933) C A MEGA1 Gen C C (0.3178 C C 243 (0.176) 376 (0.2147) C A GenC C (0.3178 C C 243 (0.176) 376 (0.2147) C A hCV596331 F9 (rs6048) LETSrec G G (0.3267 G G 70 (0.158) 87 (0.1921) G A MEGA1 dom G C (0.3043 G G233 (0.1698) 356 (0.2046) G A LETS Gen G C (0.3267 G G 70 (0.158) 87(0.1921) G A Gen G G (0.3267 G G 70 (0.158) 87 (0.1921) G A MEGA1 Gen GG (0.3043 G G 233 (0.1698) 356 (0.2046) G A Gen G G (0.3043 G G 233(0.1698) 356 (0.2046) G A hCV2892877 FGA (rs6050) LETS add T C (0.2494 CC 0 (0) 0 (0) C T MEGA1 add T C (0.2457 C C 0 (0) 0 (0) C T LETS Gen T C(0.2494 C C 0 (0) 0 (0) C T MEGA1 Gen T C (0.2457 C C 0 (0) 0 (0) C ThCV11503469

GG (rs2066854 MEGA1 add T A (0.2751 A A 174 (0.1251) 139 (0.0792) A TLETS add T A (0.2619 A A 54 (0.1241) 22 (0.0499) A T LETS Gen T A(0.2619 A A 54 (0.1241) 22 (0.0499) A T Gen T A (0.2619 A A 54 (0.1241)22 (0.0499) A T MEGA1 Gen T A (0.2751 A A 174 (0.1251) 139 (0.0792) A TGen T A (0.2751 A A 174 (0.1251) 139 (0.0792) A T hCV11503414

GG (rs2066865 MEGA1 add G A (0.2745 A A 166 (0.1231) 136 (0.0774) A GLETS add G A (0.264 A A 56 (0.1281) 24 (0.0537) A G LETS Gen G A (0.264A A 56 (0.1281) 24 (0.0537) A G Gen G A (0.264 A A 56 (0.1281) 24(0.0537) A G MEGA1 Gen G A (0.2745 A A 166 (0.1231) 136 (0.0774) A G GenG A (0.2745 A A 166 (0.1231) 136 (0.0774) A G hCV30505633 GNG12(rs753053 LETS add C T (0.0596 T T 5 (0.0113) 1 (0.0022) T C MEGA1 add CT (0.072 T T 16 (0.0115) 12 (0.0068) T C LETS Gen C T (0.0596 T T 5(0.0113) 1 (0.0022) T C Gen C T (0.0596 T T 5 (0.0113) 1 (0.0022) T CMEGA1 Gen C T (0.072 T T 16 (0.0115) 12 (0.0068) T C Gen C T (0.072 T T16 (0.0115) 12 (0.0068) T C hCV8717873 GP6 (rs1613662 MEGA1 add G G(0.193 G G 45 (0.0324) 61 (0.0349) G A LETS add G G (0.1998 G G 10(0.0226) 19 (0.0419) G A LETS Gen G G (0.1998 G G 10 (0.0226) 19(0.0419) G A Gen G G (0.1998 G G 10 (0.0226) 19 (0.0419) G A MEGA1 Gen GG (0.193 G G 45 (0.0324) 61 (0.0349) G A Gen G G (0.193 G G 45 (0.0324)61 (0.0349) G A hCV1376342 GP6 (rs1654416 LETS Gen C C (0.2141 C C 15(0.0339) 26 (0.0574) C T MEGA1 rec C C (0.203 C C 49 (0.0358) 66(0.0376) C T LETS Gen C C (0.2141 C C 15 (0.0339) 26 (0.0574) C T Gen CC (0.2141 C C 15 (0.0339) 26 (0.0574) C T MEGA1 Gen C C (0.203 C C 49(0.0358) 66 (0.0376) C T Gen C C (0.203 C C 49 (0.0358) 66 (0.0376) C ThCV8717893 GP6 (rs1671192 LETS Gen A A (0.2141 A A 15 (0.0339) 26(0.0574) A G MEGA1 rec A A (0.2027 A A 51 (0.0367) 64 (0.0364) A G LETSGen A A (0.2141 A A 15 (0.0339) 26 (0.0574) A G Gen A A (0.2141 A A 15(0.0339) 26 (0.0574) A G MEGA1 Gen A A (0.2027 A A 51 (0.0367) 64(0.0364) A G Gen A A (0.2027 A A 51 (0.0367) 64 (0.0364) A G hCV2575036RB10 (rs344327 LETS add G G (0.0265 G G 0 (0) 0 (0) G A MEGA1 add A G(0.0174 G G 1 (0.0007) 0 (0) G A LETS Gen G G (0.0265 G G 0 (0) 0 (0) GA MEGA1 Gen A G (0.0174 G G 1 (0.0007) 0 (0) G A Gen A G (0.0174 G G 1(0.0007) 0 (0) G A hCV2699725 CY1B2 (rs11841 LETS Gen G C (0.0234 C C 3(0.0069) 1 (0.0022) C G MEGA1 Gen C G (0.0307 G G 4 (0.0029) 5 (0.0028)G C LETS Gen G C (0.0234 C C 3 (0.0069) 1 (0.0022) C G Gen G C (0.0234 CC 3 (0.0069) 1 (0.0022) C G MEGA1 Gen C G (0.0307 G G 4 (0.0029) 5(0.0028) G C Gen C G (0.0307 G G 4 (0.0029) 5 (0.0028) G C hCV25995678hCV25995678 LETS add C C (0.1117 C C 4 (0.009) 8 (0.0177) C T MEGA1 domC C (0.0891 C C 5 (0.0036) 17 (0.0097) C T LETS Gen C C (0.1117 C C 4(0.009) 8 (0.0177) C T Gen C C (0.1117 C C 4 (0.009) 8 (0.0177) C TMEGA1 Gen C C (0.0891 C C 5 (0.0036) 17 (0.0097) C T Gen C C (0.0891 C C5 (0.0036) 17 (0.0097) C T hCV25996277 hCV25996277 LETS add T T (0.1126T T 4 (0.009) 8 (0.0177) T A MEGA1 Gen T T (0.0904 T T 5 (0.0036) 20(0.0114) T A LETS Gen T T (0.1126 T T 4 (0.009) 8 (0.0177) T A Gen T T(0.1126 T T 4 (0.009) 8 (0.0177) T A MEGA1 Gen T T (0.0904 T T 5(0.0036) 20 (0.0114) T A Gen T T (0.0904 T T 5 (0.0036) 20 (0.0114) T AhCV31199195 TD10 (rs108502 LETS dom A C (0.1534 C C 12 (0.0271) 14(0.0309) C A MEGA1 dom A C (0.1683 C C 52 (0.0375) 52 (0.0297) C A LETSGen A C (0.1534 C C 12 (0.0271) 14 (0.0309) C A Gen A C (0.1534 C C 12(0.0271) 14 (0.0309) C A MEGA1 Gen A C (0.1683 C C 52 (0.0375) 52(0.0297) C A Gen A C (0.1683 C C 52 (0.0375) 52 (0.0297) C A hCV27502514

LF3 (rs379653

MEGA1 dom G A (0.1584 A A 44 (0.0318) 45 (0.0257) A G LETS dom G A(0.1678 A A 17 (0.0384) 15 (0.0331) A G LETS Gen G A (0.1678 A A 17(0.0384) 15 (0.0331) A G Gen G A (0.1678 A A 17 (0.0384) 15 (0.0331) A GMEGA1 Gen G A (0.1584 A A 44 (0.0318) 45 (0.0257) A G Gen G A (0.1584 AA 44 (0.0318) 45 (0.0257) A G hCV11786258 _KB1 (rs425330 LETS Gen G A(0.4156 A A 83 (0.1886) 83 (0.1844) A G MEGA1 Gen G A (0.3933 A A 271(0.1948) 282 (0.1609) A G LETS Gen G A (0.4156 A A 83 (0.1886) 83(0.1844) A G Gen G A (0.4156 A A 83 (0.1886) 83 (0.1844) A G MEGA1 Gen GA (0.3933 A A 271 (0.1948) 282 (0.1609) A G Gen G A (0.3933 A A 271(0.1948) 282 (0.1609) A G hCV540410 ASP1 (rs60952

LETS Gen T A (0.0552 A A 2 (0.0045) 4 (0.0088) A T MEGA1 Gen T A (0.0644A A 15 (0.0108) 5 (0.0028) A T LETS Gen T A (0.0552 A A 2 (0.0045) 4(0.0088) A T Gen T A (0.0552 A A 2 (0.0045) 4 (0.0088) A T MEGA1 Gen T A(0.0644 A A 15 (0.0108) 5 (0.0028) A T Gen T A (0.0644 A A 15 (0.0108) 5(0.0028) A T hDV70662128 129656 (rs1704

LETS add G A (0.0243 A A 0 (0) 0 (0) A G MEGA1 add G A (0.0259 A A 5(0.0036) 4 (0.0023) A G LETS Gen G A (0.0243 A A 0 (0) 0 (0) A G MEGA1Gen G A (0.0259 A A 5 (0.0036) 4 (0.0023) A G Gen G A (0.0259 A A 5(0.0036) 4 (0.0023) A G hCV11541681 200420 (rs2001 MEGA1 add G C (0.3707C C 228 (0.1638) 243 (0.1385) C G LETS add G C (0.3841 C C 81 (0.1828)60 (0.1325) C G LETS Gen G C (0.3841 C C 81 (0.1828) 60 (0.1325) C G GenG C (0.3841 C C 81 (0.1828) 60 (0.1325) C G MEGA1 Gen G C (0.3707 C C228 (0.1638) 243 (0.1385) C G Gen G C (0.3707 C C 228 (0.1638) 243(0.1385) C G hCV2706410 387646 (rs7896 LETS Gen T C (0.2279 C C 33(0.0747) 30 (0.0664) C T MEGA1 Gen T C (0.2459 C C 86 (0.0629) 121(0.0689) C T LETS Gen T C (0.2279 C C 33 (0.0747) 30 (0.0664) C T Gen TC (0.2279 C C 33 (0.0747) 30 (0.0664) C T MEGA1 Gen T C (0.2459 C C 86(0.0629) 121 (0.0689) C T Gen T C (0.2459 C C 86 (0.0629) 121 (0.0689) CT hCV1547677 646030 (rs6505 LETS add A G (0.0089 G G 0 (0) 0 (0) G AMEGA1 add A G (0.0168 G G 15 (0.011) 6 (0.0034) G A LETS Gen A G (0.0089G G 0 (0) 0 (0) G A MEGA1 Gen A G (0.0168 G G 15 (0.011) 6 (0.0034) G AGen A G (0.0168 G G 15 (0.011) 6 (0.0034) G A hCV8827309 728221 (rs1110LETS add C T (0.1029 T T 11 (0.0251) 5 (0.0111) T C MEGA1 add C T(0.1204 T T 21 (0.0152) 24 (0.0139) T C LETS Gen C T (0.1029 T T 11(0.0251) 5 (0.0111) T C Gen C T (0.1029 T T 11 (0.0251) 5 (0.0111) T CMEGA1 Gen C T (0.1204 T T 21 (0.0152) 24 (0.0139) T C Gen C T (0.1204 TT 21 (0.0152) 24 (0.0139) T C hCV2103392 728284 (rs1250

LETS dom T T (0.3606 T T 49 (0.1109) 67 (0.1482) T C MEGA1 dom T T(0.3796 T T 153 (0.1138) 252 (0.1438) T C LETS Gen T T (0.3606 T T 49(0.1109) 67 (0.1482) T C Gen T T (0.3606 T T 49 (0.1109) 67 (0.1482) T CMEGA1 Gen T T (0.3796 T T 153 (0.1138) 252 (0.1438) T C Gen T T (0.3796T T 153 (0.1138) 252 (0.1438) T C hCV3230136 728284 (rs1311

MEGA1 rec A A (0.2789 A A 75 (0.054) 130 (0.0743) A G LETS rec A A(0.271 A A 31 (0.0703) 31 (0.0686) A G LETS Gen A A (0.271 A A 31(0.0703) 31 (0.0686) A G Gen A A (0.271 A A 31 (0.0703) 31 (0.0686) A GMEGA1 Gen A A (0.2789 A A 75 (0.054) 130 (0.0743) A G Gen A A (0.2789 AA 75 (0.054) 130 (0.0743) A G hCV3230131 728284 (rs1313

LETS rec C C (0.2705 C C 31 (0.0701) 31 (0.0687) C T MEGA1 rec C C(0.2817 C C 74 (0.0532) 134 (0.0765) C T LETS Gen C C (0.2705 C C 31(0.0701) 31 (0.0687) C T Gen C C (0.2705 C C 31 (0.0701) 31 (0.0687) C TMEGA1 Gen C C (0.2817 C C 74 (0.0532) 134 (0.0765) C T Gen C C (0.2817 CC 74 (0.0532) 134 (0.0765) C T hCV29821005 728284 (rs6552 LETS Gen C T(0.2056 T T 20 (0.0455) 19 (0.0422) T C MEGA1 Gen C T (0.1943 T T 62(0.0461) 77 (0.0439) T C LETS Gen C T (0.2056 T T 20 (0.0455) 19(0.0422) T C Gen C T (0.2056 T T 20 (0.0455) 19 (0.0422) T C MEGA1 Gen CT (0.1943 T T 62 (0.0461) 77 (0.0439) T C Gen C T (0.1943 T T 62(0.0461) 77 (0.0439) T C hCV32209621 728284 (rs6552 LETS Gen G G (0.4766G G 91 (0.2063) 113 (0.2517) G A MEGA1 Gen G G (0.4997 G G 305 (0.2261)450 (0.2564) G A LETS Gen G G (0.4766 G G 91 (0.2063) 113 (0.2517) G AGen G G (0.4766 G G 91 (0.2063) 113 (0.2517) G A MEGA1 Gen G G (0.4997 GG 305 (0.2261) 450 (0.2564) G A Gen G G (0.4997 G G 305 (0.2261) 450(0.2564) G A hCV32209620 728284 (rs6552 LETS dom T C (0.2073 C C 23(0.0523) 21 (0.0466) C T MEGA1 dom T C (0.1947 C C 62 (0.0463) 76(0.0436) C T LETS Gen T C (0.2073 C C 23 (0.0523) 21 (0.0466) C T Gen TC (0.2073 C C 23 (0.0523) 21 (0.0466) C T MEGA1 Gen T C (0.1947 C C 62(0.0463) 76 (0.0436) C T Gen T C (0.1947 C C 62 (0.0463) 76 (0.0436) C ThCV916107

729138 (rs670

LETS add T T (0.3554 T T 41 (0.0928) 61 (0.1347) T C MEGA1 add T T(0.3571 T T 149 (0.1071) 238 (0.1361) T C LETS Gen T T (0.3554 T T 41(0.0928) 61 (0.1347) T C Gen T T (0.3554 T T 41 (0.0928) 61 (0.1347) T CMEGA1 Gen T T (0.3571 T T 149 (0.1071) 238 (0.1361) T C Gen T T (0.3571T T 149 (0.1071) 238 (0.1361) T C hCV30922162 729672 (rs4334 LETS add CT (0.287 T T 50 (0.1131) 29 (0.064) T C MEGA1 add C T (0.2889 T T 132(0.0951) 133 (0.0758) T C LETS Gen C T (0.287 T T 50 (0.1131) 29 (0.064)T C Gen C T (0.287 T T 50 (0.1131) 29 (0.064) T C MEGA1 Gen C T (0.2889T T 132 (0.0951) 133 (0.0758) T C Gen C T (0.2889 T T 132 (0.0951) 133(0.0758) T C hCV7504118

729672 (rs967

MEGA1 add A G (0.2773 G G 123 (0.0887) 120 (0.0683) G A LETS add A G(0.2792 G G 44 (0.0995) 29 (0.064) G A LETS Gen A G (0.2792 G G 44(0.0995) 29 (0.064) G A Gen A G (0.2792 G G 44 (0.0995) 29 (0.064) G AMEGA1 Gen A G (0.2773 G G 123 (0.0887) 120 (0.0683) G A Gen A G (0.2773G G 123 (0.0887) 120 (0.0683) G A hCV11633415

730144 (rs4262 MEGA1 add C C (0.0798 C C 6 (0.0043) 11 (0.0063) C T LETSadd C C (0.083 C C 0 (0) 4 (0.0088) C T LETS Gen C C (0.083 C C 0 (0) 4(0.0088) C T Gen C C (0.083 C C 0 (0) 4 (0.0088) C T MEGA1 Gen C C(0.0798 C C 6 (0.0043) 11 (0.0063) C T Gen C C (0.0798 C C 6 (0.0043) 11(0.0063) C T hCV2494846 JZP1 (rs376540 MEGA1 rec T G (0.1657 G G 55(0.0395) 45 (0.0257) G T LETS rec T G (0.1416 G G 21 (0.0475) 10(0.0221) G T LETS Gen T G (0.1416 G G 21 (0.0475) 10 (0.0221) G T Gen TG (0.1416 G G 21 (0.0475) 10 (0.0221) G T MEGA1 Gen T G (0.1657 G G 55(0.0395) 45 (0.0257) G T Gen T G (0.1657 G G 55 (0.0395) 45 (0.0257) G ThCV25752810 IDN1 (rs470755

MEGA1 add A C (0.0191 C C 7 (0.0051) 4 (0.0023) C A LETS add A C (0.0144C C 3 (0.0068) 1 (0.0022) C A LETS Gen A C (0.0144 C C 3 (0.0068) 1(0.0022) C A Gen A C (0.0144 C C 3 (0.0068) 1 (0.0022) C A MEGA1 Gen A C(0.0191 C C 7 (0.0051) 4 (0.0023) C A Gen A C (0.0191 C C 7 (0.0051) 4(0.0023) C A hCV16170613 MET (rs2237712 MEGA1 add A G (0.0313 G G 3(0.0022) 1 (0.0006) G A LETS add A G (0.0299 G G 4 (0.009) 0 (0) G ALETS Gen A G (0.0299 G G 4 (0.009) 0 (0) G A Gen A G (0.0299 G G 4(0.009) 0 (0) G A MEGA1 Gen A G (0.0313 G G 3 (0.0022) 1 (0.0006) G AGen A G (0.0313 G G 3 (0.0022) 1 (0.0006) G A hCV11726971

FIA (rs2065841 LETS Gen A G (0.1512 G G 23 (0.0519) 10 (0.0221) G AMEGA1 Gen A G (0.1927 G G 51 (0.0369) 75 (0.0428) G A LETS Gen A G(0.1512 G G 23 (0.0519) 10 (0.0221) G A Gen A G (0.1512 G G 23 (0.0519)10 (0.0221) G A MEGA1 Gen A G (0.1927 G G 51 (0.0369) 75 (0.0428) G AGen A G (0.1927 G G 51 (0.0369) 75 (0.0428) G A hCV30747430 R1I2(rs1171221 MEGA1 add C T (0.1852 T T 76 (0.0563) 65 (0.037) T C LETS addC T (0.1519 T T 26 (0.0591) 11 (0.0244) T C LETS Gen C T (0.1519 T T 26(0.0591) 11 (0.0244) T C Gen C T (0.1519 T T 26 (0.0591) 11 (0.0244) T CMEGA1 Gen C T (0.1852 T T 76 (0.0563) 65 (0.037) T C Gen C T (0.1852 T T76 (0.0563) 65 (0.037) T C hCV263841 R1I2 (rs152312 LETS add A C (0.3296C C 88 (0.2018) 49 (0.1106) C A MEGA1 add A C (0.3907 C C 250 (0.1788)261 (0.1485) C A LETS Gen A C (0.3296 C C 88 (0.2018) 49 (0.1106) C AGen A C (0.3296 C C 88 (0.2018) 49 (0.1106) C A MEGA1 Gen A C (0.3907 CC 250 (0.1788) 261 (0.1485) C A Gen A C (0.3907 C C 250 (0.1788) 261(0.1485) C A hCV4041 NR3C1 (rs6190) MEGA1 dom C T (0.0268 T T 4 (0.0029)1 (0.0006) T C LETS dom C T (0.031 T T 1(0.0023) 1 (0.0022) T C LETS GenC T (0.031 T T 1 (0.0023) 1 (0.0022) T C Gen C T (0.031 T T 1 (0.0023) 1(0.0022) T C MEGA1 Gen C T (0.0268 T T 4 (0.0029) 1 (0.0006) T C Gen C T(0.0268 T T 4 (0.0029) 1 (0.0006) T C hCV2915511

BSL1 (rs62753

LETS Gen T C (0.0265 C C 3 (0.0068) 1 (0.0022) CT MEGA1 Gen T C (0.0387C C 13 (0.0093) 5 (0.0028) C T LETS Gen T C (0.0265 C C 3 (0.0068) 1(0.0022) C T Gen T C (0.0265 C C 3 (0.0068) 1 (0.0022) C T MEGA1 Gen T C(0.0387 C C 13 (0.0093) 5 (0.0028) C T Gen T C (0.0387 C C 13 (0.0093) 5(0.0028) C T hCV16177220

DZ1 (rs226691

MEGA1 add T T (0.2098 T T 125 (0.0899) 214 (0.122) T C LETS add T T(0.213 T T 35 (0.079) 54 (0.1192) T C LETS Gen T T (0.213 T T 35 (0.079)54 (0.1192) T C Gen T T (0.213 T T 35 (0.079) 54 (0.1192) T C MEGA1 GenT T (0.2098 T T 125 (0.0899) 214 (0.122) T C Gen T T (0.2098 T T 125(0.0899) 214 (0.122) T C hCV7584272 R1B1 (rs153692 LETS Gen G A (0.2367A A 26 (0.059) 24 (0.0531) A G MEGA1 dom G A (0.2396 A A 83 (0.0607) 98(0.0558) A G LETS Gen G A (0.2367 A A 26 (0.059) 24 (0.0531) A G Gen G A(0.2367 A A 26 (0.059) 24 (0.0531) A G MEGA1 Gen G A (0.2396 A A 83(0.0607) 98 (0.0558) A G Gen G A (0.2396 A A 83 (0.0607) 98 (0.0558) A GhCV9327878 R7G1 (rs221765 MEGA1 add C G (0.3169 G G 180 (0.1316) 190(0.1082) G C LETS add C G (0.3069 G G 61 (0.1386) 45 (0.1004) G C LETSGen C G (0.3069 G G 61 (0.1386) 45 (0.1004) G C Gen C G (0.3069 G G 61(0.1386) 45 (0.1004) G C MEGA1 Gen C G (0.3169 G G 180 (0.1316) 190(0.1082) G C Gen C G (0.3169 G G 180 (0.1316) 190 (0.1082) G ChCV15990789 TOG (rs235546 MEGA1 rec A A (0.4036 A A 220 (0.1614) 279(0.1592) A G LETS rec A A (0.4446 A A 75 (0.1697) 80 (0.1774) A G LETSGen A A (0.4446 A A 75 (0.1697) 80 (0.1774) A G Gen A A (0.4446 A A 75(0.1697) 80 (0.1774) A G MEGA1 Gen A A (0.4036 A A 220 (0.1614) 279(0.1592) A G Gen A A (0.4036 A A 220 (0.1614) 279 (0.1592) A GhCV8361354 ANX1 (rs113880 LETS Gen A A (0.4007 A A 48 (0.1084) 70(0.1545) A C MEGA1 Gen A A (0.3793 A A 207 (0.1491) 227 (0.1296) A CLETS Gen A A (0.4007 A A 48 (0.1084) 70 (0.1545) A C Gen A A (0.4007 A A48 (0.1084) 70 (0.1545) A C MEGA1 Gen A A (0.3793 A A 207 (0.1491) 227(0.1296) A C Gen A A (0.3793 A A 207 (0.1491) 227 (0.1296) A ChCV30500334 ACTR3 (rs61286 LETS add A A (0.4172 A A 59 (0.1332) 74(0.1634) A G MEGA1 add A A (0.3969 A A 185 (0.1358) 285 (0.1624) A GLETS Gen A A (0.4172 A A 59 0.1332) 74 (0.1634) A G Gen A A (0.4172 A A59 (0.1332) 74 (0.1634) A G MEGA1 Gen A A (0.3969 A A 185 (0.1358) 285(0.1624) A G Gen A A (0.3969 A A 185 (0.1358) 285 (0.1624) A GhCV27474984 K3R1 (rs375666 MEGA1 add G A (0.4412 A A 293 (0.2108) 362(0.2067) A G LETS add G A (0.449 A A 110 (0.2489) 87 (0.1929) A G LETSGen G A (0.449 A A 110 (0.2489) 87 (0.1929) A G Gen G A (0.449 A A 110(0.2489) 87 (0.1929) A G MEGA1 Gen G A (0.4412 A A 293 (0.2108) 362(0.2067) A G Gen G A (0.4412 A A 293 (0.2108) 362 (0.2067) A GhCV7625318 EKHG4 (rs38681 LETS Gen G A (0.0629 A A 2 (0.0045) 4 (0.0088)A G MEGA1 Gen G A (0.0764 A A 13 (0.0094) 16 (0.0091) A G LETS Gen G A(0.0629 A A 2 (0.0045) 4 (0.0088) A G Gen G A (0.0629 A A 2 (0.0045) 4(0.0088) A G MEGA1 Gen G A (0.0764 A A 13 (0.0094) 16 (0.0091) A G Gen GA (0.0764 A A 13 (0.0094) 16 (0.0091) A G hCV8598986

LR1A (rs48322

LETS rec T T (0.3186 T T 28 (0.0633) 45 (0.0996) T C MEGA1 rec T T(0.2873 T T 119 (0.0858) 154 (0.0882) T C LETS Gen T T (0.3186 T T 28(0.0633) 45 (0.0996) T C Gen T T (0.3186 T T 28 (0.0633) 45 (0.0996) T CMEGA1 Gen T T (0.2873 T T 119 (0.0858) 154 (0.0882) T C Gen T T (0.2873T T 119 (0.0858) 154 (0.0882) T C hCV926518 P2R5C (rs7467

LETS Gen T G (0.0896 G G 4 (0.009) 5 (0.0111) G T MEGA1 Gen T G (0.0994G G 16 (0.0117) 26 (0.0148) G T LETS Gen T G (0.0896 G G 4 (0.009) 5(0.0111) G T Gen T G (0.0896 G G 4 (0.009) 5 (0.0111) G T MEGA1 Gen T G(0.0994 G G 16 (0.0117) 26 (0.0148) G T Gen T G (0.0994 G G 16 (0.0117)26 (0.0148) G T hCV1841975 ROC (rs179981

LETS Gen A T (0.427 T T 100 (0.2262) 81 (0.1792) T A MEGA1 Gen A T(0.4356 T T 323 (0.2327) 329 (0.1883) T A LETS Gen A T (0.427 T T 100(0.2262) 81 (0.1792) T A Gen A T (0.427 T T 100 (0.2262) 81 (0.1792) T AMEGA1 Gen A T (0.4356 T T 323 (0.2327) 329 (0.1883) T A Gen A T (0.4356T T 323 (0.2327) 329 (0.1883) T A hCV8957432 RAC2 (rs6572) MEGA1 rec G C(0.4364 C C 308 (0.2217) 334 (0.1905) C G LETS rec G C (0.4458 C C 99(0.2245) 77 (0.1704) C G LETS Gen G C (0.4458 C C 99 (0.2245) 77(0.1704) C G Gen G C (0.4458 C C 99 (0.2245) 77 (0.1704) C G MEGA1 Gen GC (0.4364 C C 308 (0.2217) 334 (0.1905) C G Gen G C (0.4364 C C 308(0.2217) 334 (0.1905) C G hCV29271569 DH13 (rs162697 LETS add C C(0.1954 C C 9 (0.0204) 17 (0.0375) C T MEGA1 add C C (0.1867 C C 43(0.031) 60 (0.0342) C T LETS Gen C C (0.1954 C C 9 (0.0204) 17 (0.0375)C T Gen C C (0.1954 C C 9 (0.0204) 17 (0.0375) C T MEGA1 Gen C C (0.1867C C 43 (0.031) 60 (0.0342) C T Gen C C (0.1867 C C 43 (0.031) 60(0.0342) C T hCV8703249 DH13 (rs16544 LETS add T T (0.1898 T T 10(0.0226) 17 (0.0375) T G MEGA1 add T T (0.1879 T T 41 (0.0296) 64(0.0364) T G LETS Gen T T (0.1898 T T 10 (0.0226) 17 (0.0375) T G Gen TT (0.1898 T T 10 (0.0226) 17 (0.0375) T G MEGA1 Gen T T (0.1879 T T 41(0.0296) 64 (0.0364) T G Gen T T (0.1879 T T 41 (0.0296) 64 (0.0364) T GhCV8717752 DH13 (rs167121 LETS add A A (0.1892 A A 7 (0.0158) 17(0.0376) A G MEGA1 rec A A (0.1774 A A 36 (0.026) 52 (0.0297) A G LETSGen A A (0.1892 A A 7 (0.0158) 17 (0.0376) A G Gen A A (0.1892 A A 7(0.0158) 17 (0.0376) A G MEGA1 Gen A A (0.1774 A A 36 (0.026) 52(0.0297) A G Gen A A (0.1774 A A 36 (0.026) 52 (0.0297) A G hCV11975296SELP (rs6131) MEGA1 add C T (0.1818 T T 63 (0.0453) 66 (0.0377) T C LETSadd C T (0.1777 T T 27 (0.0611) 20 (0.0442) T C LETS Gen C T (0.1777 T T27 (0.0611) 20 (0.0442) T C Gen C T (0.1777 T T 27 (0.0611) 20 (0.0442)T C MEGA1 Gen C T (0.1818 T T 63 (0.0453) 66 (0.0377) T C Gen C T(0.1818 T T 63 (0.0453) 66 (0.0377) T C hCV9596963 ERPINA5 (rs611 LETSdom G G (0.3831 G G 38 (0.0874) 60 (0.1336) G A MEGA1 dom G G (0.3441 GG 137 (0.0988) 214 (0.1224) G A LETS Gen G G (0.3831 G G 38 (0.0874) 60(0.1336) G A Gen G G (0.3831 G G 38 (0.0874) 60 (0.1336) G A MEGA1 Gen GG (0.3441 G G 137 (0.0988) 214 (0.1224) G A Gen G G (0.3441 G G 137(0.0988) 214 (0.1224) G A hCV16180170 RPINC1 (rs2227

MEGA1 add C T (0.0892 T T 22 (0.0158) 15 (0.0085) T C LETS add C T(0.0863 T T 6 (0.0135) 4 (0.0088) T C LETS Gen C T (0.0863 T T 6(0.0135) 4 (0.0088) T C Gen C T (0.0863 T T 6 (0.0135) 4 (0.0088) T CMEGA1 Gen C T (0.0892 T T 22 (0.0158) 15 (0.0085) T C Gen C T (0.0892 TT 22 (0.0158) 15 (0.0085) T C hCV1650632 ERPINC1 (rs587 MEGA1 Gen T C(0.3391 C C 191 (0.1426) 197 (0.1126) C T LETS Gen T C (0.3213 C C 49(0.1119) 56 (0.1258) C T LETS Gen T C (0.3213 C C 49 (0.1119) 56(0.1258) C T Gen T C (0.3213 C C 49 (0.1119) 56 (0.1258) C T MEGA1 Gen TC (0.3391 C C 191 (0.1426) 197 (0.1126) C T Gen T C (0.3391 C C 191(0.1426) 197 (0.1126) C T hCV3216426 RS2IP (rs73157 LETS dom T T (0.5022T T 87 (0.1977) 119 (0.2662) T A MEGA1 dom T T (0.4909 T T 301 (0.2155)441 (0.251) T A LETS Gen T T (0.5022 T T 87 (0.1977) 119 (0.2662) T AGen T T (0.5022 T T 87 (0.1977) 119 (0.2662) T A MEGA1 Gen T T (0.4909 TT 301 (0.2155) 441 (0.251) T A Gen T T (0.4909 T T 301 (0.2155) 441(0.251) T A hCV25602230 IRT6 (rs724623 MEGA1 add T G (0.0108 G G 4(0.0029) 1 (0.0006) G T LETS add T G (0.0055 G G 2 (0.0045) 0 (0) G TLETS Gen T G (0.0055 G G 2 (0.0045) 0 (0) G T Gen T G (0.0055 G G 2(0.0045) 0 (0) G T MEGA1 Gen T G (0.0108 G G 4 (0.0029) 1 (0.0006) G TGen T G (0.0108 G G 4 (0.0029) 1 (0.0006) G T hCV2086329

ARC (rs495848 MEGA1 rec A G (0.4219 G G 298 (0.2152) 296 (0.1688) G ALETS rec A G (0.4183 G G 104 (0.2348) 76 (0.1678) G A LETS Gen A G(0.4183 G G 104 (0.2348) 76 (0.1678) G A Gen A G (0.4183 G G 104(0.2348) 76 (0.1678) G A MEGA1 Gen A G (0.4219 G G 298 (0.2152) 296(0.1688) G A Gen A G (0.4219 G G 298 (0.2152) 296 (0.1688) G AhCV11466393 TACR1 (rs881) LETS add G G (0.1953 G G 10 (0.0228) 17(0.0384) G C MEGA1 add G G (0.1746 G G 32 (0.023) 52 (0.0297) G C LETSGen G G (0.1953 G G 10 (0.0228) 17 (0.0384) G C Gen G G (0.1953 G G 10(0.0228) 17 (0.0384) G C MEGA1 Gen G G (0.1746 G G 32 (0.023) 52(0.0297) G C Gen G G (0.1746 G G 32 (0.023) 52 (0.0297) G C hCV3216649AF1B (rs105456 LETS dom G A (0.2971 A A 50 (0.1134) 47 (0.1042) A GMEGA1 dom G A (0.3179 A A 160 (0.115) 191 (0.109) A G LETS Gen G A(0.2971 A A 50 (0.1134) 47 (0.1042) A G Gen G A (0.2971 A A 50 (0.1134)47 (0.1042) A G MEGA1 Gen G A (0.3179 A A 160 (0.115) 191 (0.109) A GGen G A (0.3179 A A 160 (0.115) 191 (0.109) A G hCV470708 IBS2 (rs109454

LETS add G T (0.2838 T T 50 (0.1131) 38 (0.0843) T G MEGA1 Gen G T(0.3005 T T 152 (0.109) 153 (0.0873) T G LETS Gen G T (0.2838 T T 50(0.1131) 38 (0.0843) T G Gen G T (0.2838 T T 50 (0.1131) 38 (0.0843) T GMEGA1 Gen G T (0.3005 T T 152 (0.109) 153 (0.0873) T G Gen G T (0.3005 TT 152 (0.109) 153 (0.0873) T G hCV3272537 IAM1 (rs497689 LETS dom T A(0.4281 A A 100 (0.2268) 90 (0.1991) A T MEGA1 dom T A (0.4287 A A 277(0.2003) 347 (0.1989) A T LETS Gen T A (0.4281 A A 100 (0.2268) 90(0.1991) A T Gen T A (0.4281 A A 100 (0.2268) 90 (0.1991) A T MEGA1 GenT A (0.4287 A A 277 (0.2003) 347 (0.1989) A T Gen T A (0.4287 A A 277(0.2003) 347 (0.1989) A T hCV27833944 IFSF4 (rs67023

LETS add T C (0.0856 C C 5 (0.0113) 3 (0.0067) C T MEGA1 add T C (0.0901C C 25 (0.018) 16 (0.0091) C T LETS Gen T C (0.0856 C C 5 (0.0113) 3(0.0067) C T Gen T C (0.0856 C C 5 (0.0113) 3 (0.0067) C T MEGA1 Gen T C(0.0901 C C 25 (0.018) 16 (0.0091) C T Gen T C (0.0901 C C 25 (0.018) 16(0.0091) C T hCV1723643 MODL1 (rs22013 LETS rec C C (0.2406 C C 19(0.0431) 22 (0.0488) C A MEGA1 rec C C (0.2246 C C 59 (0.0426) 95(0.0542) C A LETS Gen C C (0.2406 C C 19 (0.0431) 22 (0.0488) C A Gen CC (0.2406 C C 19 (0.0431) 22 (0.0488) C A MEGA1 Gen C C (0.2246 C C 59(0.0426) 95 (0.0542) C A Gen C C (0.2246 C C 59 (0.0426) 95 (0.0542) C AhCV7581501 SP45 (rs132371 LETS Gen G C (0.096 C C 9 (0.0203) 7 (0.0155)C G MEGA1 Gen G C (0.1142 C C 26 (0.0187) 17 (0.0097) C G LETS Gen G C(0.096 C C 9 (0.0203) 7 (0.0155) C G Gen G C (0.096 C C 9 (0.0203) 7(0.0155) C G MEGA1 Gen G C (0.1142 C C 26 (0.0187) 17 (0.0097) C G Gen GC (0.1142 C C 26 (0.0187) 17 (0.0097) C G hCV15949414

YLB (rs223462

MEGA1 rec A A (0.0496 A A 5 (0.0037) 1 (0.0006) A G LETS rec A A (0.0569A A 1 (0.0023) 0 (0) A G LETS Gen A A (0.0569 A A 1 (0.0023) 0 (0) A GGen A A (0.0569 A A 1 (0.0023) 0 (0) A G MEGA1 Gen A A (0.0496 A A 5(0.0037) 1 (0.0006) A G Gen A A (0.0496 A A 5 (0.0037) 1 (0.0006) A GhCV356522 TB41 (rs107322 LETS dom C T (0.0784 T T 6 (0.0135) 4 (0.0088)T C MEGA1 dom C T (0.0931 T T 22 (0.0159) 19 (0.0108) T C LETS Gen C T(0.0784 T T 6 (0.0135) 4 (0.0088) T C Gen C T (0.0784 T T 6 (0.0135) 4(0.0088) T C MEGA1 Gen C T (0.0931 T T 22 (0.0159) 19 (0.0108) T C Gen CT (0.0931 T T 22 (0.0159) 19 (0.0108) T C hCV25596789 JF544 (rs651013LETS add C G (0.0144 G G 2 (0.0045) 0 (0) G C MEGA1 add C G (0.0182 G G1 (0.0007) 0 (0) G C LETS Gen C G (0.0144 G G 2 (0.0045) 0 (0) G C Gen CG (0.0144 G G 2 (0.0045) 0 (0) G C MEGA1 Gen C G (0.0182 G G 1 (0.0007)0 (0) G C Gen C G (0.0182 G G 1 (0.0007) 0 (0) G C hCV25951992

INT (rs110053

MEGA1 dom C A (0.0091 A A 5 (0.0036) 1 (0.0006) A C LETS dom C A (0.0122A A 0 (0) 1 (0.0022) A C LETS Gen C A (0.0122 A A 0 (0) 1 (0.0022) A CGen C A (0.0122 A A 0 (0) 1 (0.0022) A C MEGA1 Gen C A (0.0091 A A 5(0.0036) 1 (0.0006) A C Gen C A (0.0091 A A 5 (0.0036) 1 (0.0006) A CCONTROL cnt CONTROL cnt CASE cnt (CONTROL CASE cnt (CONTROL marker annotEndpoint Model (CASE frq2 frq)2 Genot3 (CASE frq3 frq)3 hCV505733(rs11126416) LETS Gen 215 (0.4853 222 (0.4901) G G 157 (0.3544 177(0.3907) MEGA1 Gen 637 (0.4593 800 (0.4553) G G 540 (0.3893 744 (0.4234)LETS Gen 215 (0.4853 222 (0.4901) G G 157 (0.3544 177 (0.3907) Gen 215(0.4853 222 (0.4901) G G 157 (0.3544 177 (0.3907) MEGA1 Gen 637 (0.4593800 (0.4553) G G 540 (0.3893 744 (0.4234) Gen 637 (0.4593 800 (0.4553) GG 540 (0.3893 744 (0.4234) hCV2879752 (rs1244565) LETS add 227 (0.5147214 (0.4724) A A 99 (0.2245 135 (0.298) MEGA1 add 672 (0.4923 886(0.5057) A A 352 (0.2579 487 (0.278) LETS Gen 227 (0.5147 214 (0.4724) AA 99 (0.2245 135 (0.298) Gen 227 (0.5147 214 (0.4724) A A 99 (0.2245 135(0.298) MEGA1 Gen 672 (0.4923 886 (0.5057) A A 352 (0.2579 487 (0.278)Gen 672 (0.4923 886 (0.5057) A A 352 (0.2579 487 (0.278) hCV11503470(rs1800788) MEGA1 add 512 (0.3691 544 (0.3105) C C 790 (0.5696 1101(0.6284) LETS add 156 (0.3521 144 (0.3186) C C 256 (0.5779 291 (0.6438)LETS Gen 156 (0.3521 144 (0.3186) C C 256 (0.5779 291 (0.6438) Gen 156(0.3521 144 (0.3186) C C 256 (0.5779 291 (0.6438) MEGA1 Gen 512 (0.3691544 (0.3105) C C 790 (0.5696 1101 (0.6284) Gen 512 (0.3691 544 (0.3105)C C 790 (0.5696 1101 (0.6284) hCV15860433 (rs2070006) MEGA1 add 689(0.4957 832 (0.4746) C C 405 (0.2914 624 (0.356) LETS add 211 (0.4785217 (0.4822) C C 135 (0.3061 161 (0.3578) LETS Gen 211 (0.4785 217(0.4822) C C 135 (0.3061 161 (0.3578) Gen 211 (0.4785 217 (0.4822) C C135 (0.3061 161 (0.3578) MEGA1 Gen 689 (0.4957 832 (0.4746) C C 405(0.2914 624 (0.356) Gen 689 (0.4957 832 (0.4746) C C 405 (0.2914 624(0.356) hCV2744023 (rs369328) LETS add 229 (0.5169 232 (0.5133) G G 98(0.2212 133 (0.2942) MEGA1 add 680 (0.4871 872 (0.4966) G G 346 (0.2479480 (0.2733) LETS Gen 229 (0.5169 232 (0.5133) G G 98 (0.2212 133(0.2942) Gen 229 (0.5169 232 (0.5133) G G 98 (0.2212 133 (0.2942) MEGA1Gen 680 (0.4871 872 (0.4966) G G 346 (0.2479 480 (0.2733) Gen 680(0.4871 872 (0.4966) G G 346 (0.2479 480 (0.2733) hCV27477533(rs3756008) MEGA1 add 691 (0.4953 832 (0.4749) A A 397 (0.2846 624(0.3562) LETS add 212 (0.4796 200 (0.4425) A A 129 (0.2919 164 (0.3628)LETS Gen 212 (0.4796 200 (0.4425) A A 129 (0.2919 164 (0.3628) Gen 212(0.4796 200 (0.4425) A A 129 (0.2919 164 (0.3628) MEGA1 Gen 691 (0.4953832 (0.4749) A A 397 (0.2846 624 (0.3562) Gen 691 (0.4953 832 (0.4749) AA 397 (0.2846 624 (0.3562) hCV949676 (rs480802) MEGA1 Gen 440 (0.3262559 (0.3213) T T 826 (0.6123 1104 (0.6345) LETS Gen 138 (0.3151 139(0.3075) T T 271 (0.6187 296 (0.6549) LETS Gen 138 (0.3151 139 (0.3075)T T 271 (0.6187 296 (0.6549) Gen 138 (0.3151 139 (0.3075) T T 271(0.6187 296 (0.6549) MEGA1 Gen 440 (0.3262 559 (0.3213) T T 826 (0.61231104 (0.6345) Gen 440 (0.3262 559 (0.3213) T T 826 (0.6123 1104 (0.6345)hCV27904396 (rs4829996) LETS rec 92 (0.2081 111 (0.245) G G 286 (0.6471263 (0.5806) MEGA1 Gen 300 (0.2158 346 (0.1977) G G 859 (0.618 1069(0.6109) LETS Gen 92 (0.2081 111 (0.245) G G 286 (0.6471 263 (0.5806)Gen 92 (0.2081 111 (0.245) G G 286 (0.6471 263 (0.5806) MEGA1 Gen 300(0.2158 346 (0.1977) G G 859 (0.618 1069 (0.6109) Gen 300 (0.2158 346(0.1977) G G 859 (0.618 1069 (0.6109) hCV837462 (rs528088) LETS Gen 70(0.1584 68 (0.1504) A A 364 (0.8235 382 (0.8451) MEGA1 dom 193 (0.1385237 (0.1354) A A 1196 (0.858 1495 (0.8538) LETS Gen 70 (0.1584 68(0.1504) A A 364 (0.8235 382 (0.8451) Gen 70 (0.1584 68 (0.1504) A A 364(0.8235 382 (0.8451) MEGA1 Gen 193 (0.1385 237 (0.1354) A A 1196 (0.8581495 (0.8538) Gen 193 (0.1385 237 (0.1354) A A 1196 (0.858 1495 (0.8538)hCV30440155 (rs6699146) LETS add 204 (0.4647 207 (0.458) G G 135 (0.3075161 (0.3562) MEGA1 add 651 (0.4855 865 (0.4951) G G 369 (0.2752 538(0.308) LETS Gen 204 (0.4647 207 (0.458) G G 135 (0.3075 161 (0.3562)Gen 204 (0.4647 207 (0.458) G G 135 (0.3075 161 (0.3562) MEGA1 Gen 651(0.4855 865 (0.4951) G G 369 (0.2752 538 (0.308) Gen 651 (0.4855 865(0.4951) G G 369 (0.2752 538 (0.308) hCV28960679 (rs6844764) LETS rec210 (0.4751 234 (0.5177) G G 158 (0.3575 136 (0.3009) MEGA1 dom 690(0.4964 814 (0.467) G G 467 (0.336 571 (0.3276) LETS Gen 210 (0.4751 234(0.5177) G G 158 (0.3575 136 (0.3009) Gen 210 (0.4751 234 (0.5177) G G158 (0.3575 136 (0.3009) MEGA1 Gen 690 (0.4964 814 (0.467) G G 467(0.336 571 (0.3276) Gen 690 (0.4964 814 (0.467) G G 467 (0.336 571(0.3276) hCV1952126 (rs7223784) LETS add 164 (0.3702 188 (0.4159) A A248 (0.5598 221 (0.4889) MEGA1 add 527 (0.3808 688 (0.3925) A A 766(0.5535 918 (0.5237) LETS Gen 164 (0.3702 188 (0.4159) A A 248 (0.5598221 (0.4889) Gen 164 (0.3702 188 (0.4159) A A 248 (0.5598 221 (0.4889)MEGA1 Gen 527 (0.3808 688 (0.3925) A A 766 (0.5535 918 (0.5237) Gen 527(0.3808 688 (0.3925) A A 766 (0.5535 918 (0.5237) hCV31749285(rs8178591) LETS rec 160 (0.3612 200 (0.4415) C C 243 (0.5485 221(0.4879) MEGA1 rec 526 (0.3781 722 (0.4123) C C 779 (0.56 903 (0.5157)LETS Gen 160 (0.3612 200 (0.4415) C C 243 (0.5485 221 (0.4879) Gen 160(0.3612 200 (0.4415) C C 243 (0.5485 221 (0.4879) MEGA1 Gen 526 (0.3781722 (0.4123) C C 779 (0.56 903 (0.5157) Gen 526 (0.3781 722 (0.4123) C C779 (0.56 903 (0.5157) hCV3187716 AGTR1 (rs5186

LETS dom 199 (0.4543 184 (0.4116) A A 195 (0.4452 224 (0.5011) MEGA1 add530 (0.3946 752 (0.4292) A A 711 (0.5294 835 (0.4766) LETS Gen 199(0.4543 184 (0.4116) A A 195 (0.4452 224 (0.5011) Gen 199 (0.4543 184(0.4116) A A 195 (0.4452 224 (0.5011) MEGA1 Gen 530 (0.3946 752 (0.4292)A A 711 (0.5294 835 (0.4766) Gen 530 (0.3946 752 (0.4292) A A 711(0.5294 835 (0.4766) hCV9493081

KT3 (rs105830

LETS add 202 (0.457 174 (0.3858) C C 190 (0.4299 245 (0.5432) MEGA1 add553 (0.4096 748 (0.4262) C C 645 (0.4778 879 (0.5009) LETS Gen 202(0.457 174 (0.3858) C C 190 (0.4299 245 (0.5432) Gen 202 (0.457 174(0.3858) C C 190 (0.4299 245 (0.5432) MEGA1 Gen 553 (0.4096 748 (0.4262)C C 645 (0.4778 879 (0.5009) Gen 553 (0.4096 748 (0.4262) C C 645(0.4778 879 (0.5009) hCV30690780

T3 (rs1073788 LETS add 177 (0.4032 142 (0.3149) A A 223 (0.508 288(0.6386) MEGA1 add 490 (0.3632 623 (0.3568) A A 745 (0.5523 1034(0.5922) LETS Gen 177 (0.4032 142 (0.3149) A A 223 (0.508 288 (0.6386)Gen 177 (0.4032 142 (0.3149) A A 223 (0.508 288 (0.6386) MEGA1 Gen 490(0.3632 623 (0.3568) A A 745 (0.5523 1034 (0.5922) Gen 490 (0.3632 623(0.3568) A A 745 (0.5523 1034 (0.5922) hCV31523557

T3 (rs1075480 LETS add 163 (0.3696 120 (0.2667) G G 254 (0.576 315 (0.7)MEGA1 add 461 (0.3415 532 (0.3028) G G 815 (0.6037 1151 (0.6551) LETSGen 163 (0.3696 120 (0.2667) G G 254 (0.576 315 (0.7) Gen 163 (0.3696120 (0.2667) G G 254 (0.576 315 (0.7) MEGA1 Gen 461 (0.3415 532 (0.3028)G G 815 (0.6037 1151 (0.6551) Gen 461 (0.3415 532 (0.3028) G G 815(0.6037 1151 (0.6551) hCV26719108

T3 (rs1092703 LETS add 216 (0.4887 202 (0.4469) T T 156 (0.3529 201(0.4447) MEGA1 add 624 (0.4636 797 (0.4575) T T 500 (0.3715 720 (0.4133)LETS Gen 216 (0.4887 202 (0.4469) T T 156 (0.3529 201 (0.4447) Gen 216(0.4887 202 (0.4469) T T 156 (0.3529 201 (0.4447) MEGA1 Gen 624 (0.4636797 (0.4575) T T 500 (0.3715 720 (0.4133) Gen 624 (0.4636 797 (0.4575) TT 500 (0.3715 720 (0.4133) hCV26719121

T3 (rs1092704 LETS add 164 (0.371 121 (0.2677) T T 253 (0.5724 316(0.6991) MEGA1 add 453 (0.3358 531 (0.3026) T T 824 (0.6108 1151(0.6558) LETS Gen 164 (0.371 121 (0.2677) T T 253 (0.5724 316 (0.6991)Gen 164 (0.371 121 (0.2677) T T 253 (0.5724 316 (0.6991) MEGA1 Gen 453(0.3358 531 (0.3026) T T 824 (0.6108 1151 (0.6558) Gen 453 (0.3358 531(0.3026) T T 824 (0.6108 1151 (0.6558) hCV26719227

T3 (rs1092706 LETS add 146 (0.3303 112 (0.2494) C C 284 (0.6425 327(0.7283) MEGA1 add 409 (0.303 478 (0.2727) C C 889 (0.6585 1224 (0.6982)LETS Gen 146 (0.3303 112 (0.2494) C C 284 (0.6425 327 (0.7283) Gen 146(0.3303 112 (0.2494) C C 284 (0.6425 327 (0.7283) MEGA1 Gen 409 (0.303478 (0.2727) C C 889 (0.6585 1224 (0.6982) Gen 409 (0.303 478 (0.2727) CC 889 (0.6585 1224 (0.6982) hCV31523638

T3 (rs1203701 LETS add 135 (0.3068 99 (0.219) G G 293 (0.6659 344(0.7611) MEGA1 add 384 (0.2844 455 (0.2594) G G 926 (0.6859 1263(0.7201) LETS Gen 135 (0.3068 99 (0.219) G G 293 (0.6659 344 (0.7611)Gen 135 (0.3068 99 (0.219) G G 293 (0.6659 344 (0.7611) MEGA1 Gen 384(0.2844 455 (0.2594) G G 926 (0.6859 1263 (0.7201) Gen 384 (0.2844 455(0.2594) G G 926 (0.6859 1263 (0.7201) hCV30690777

T3 (rs1204558 MEGA1 add 392 (0.291 451 (0.257) G G 919 (0.6823 1277(0.7276) LETS add 131 (0.3011 108 (0.2432) G G 293 (0.6736 328 (0.7387)LETS Gen 131 (0.3011 108 (0.2432) G G 293 (0.6736 328 (0.7387) Gen 131(0.3011 108 (0.2432) G G 293 (0.6736 328 (0.7387) MEGA1 Gen 392 (0.291451 (0.257) G G 919 (0.6823 1277 (0.7276) Gen 392 (0.291 451 (0.257) G G919 (0.6823 1277 (0.7276) hCV31523650

T3 (rs1204893 LETS add 163 (0.3721 130 (0.2889) C C 250 (0.5708 304(0.6756) MEGA1 add 472 (0.342 541 (0.3086) C C 834 (0.6043 1130 (0.6446)LETS Gen 163 (0.3721 130 (0.2889) C C 250 (0.5708 304 (0.6756) Gen 163(0.3721 130 (0.2889) C C 250 (0.5708 304 (0.6756) MEGA1 Gen 472 (0.342541 (0.3086) C C 834 (0.6043 1130 (0.6446) Gen 472 (0.342 541 (0.3086) CC 834 (0.6043 1130 (0.6446) hCV30690778

T3 (rs1214041 LETS add 163 (0.3713 125 (0.2772) T T 257 (0.5854 311(0.6896) MEGA1 add 443 (0.3284 553 (0.3151) T T 847 (0.6279 1150(0.6553) LETS Gen 163 (0.3713 125 (0.2772) T T 257 (0.5854 311 (0.6896)Gen 163 (0.3713 125 (0.2772) T T 257 (0.5854 311 (0.6896) MEGA1 Gen 443(0.3284 553 (0.3151) T T 847 (0.6279 1150 (0.6553) Gen 443 (0.3284 553(0.3151) T T 847 (0.6279 1150 (0.6553) hCV31523608

T3 (rs1274429 MEGA1 add 609 (0.4518 740 (0.4224) A A 553 (0.4102 815(0.4652) LETS add 202 (0.458 181 (0.4013) A A 182 (0.4127 227 (0.5033)LETS Gen 202 (0.458 181 (0.4013) A A 182 (0.4127 227 (0.5033) Gen 202(0.458 181 (0.4013) A A 182 (0.4127 227 (0.5033) MEGA1 Gen 609 (0.4518740 (0.4224) A A 553 (0.4102 815 (0.4652) Gen 609 (0.4518 740 (0.4224) AA 553 (0.4102 815 (0.4652) hCV233148

T3 (rs141712

LETS add 202 (0.456 174 (0.3841) G G 191 (0.4312 247 (0.5453) MEGA1 add573 (0.4128 745 (0.424) G G 652 (0.4697 883 (0.5026) LETS Gen 202 (0.456174 (0.3841) G G 191 (0.4312 247 (0.5453) Gen 202 (0.456 174 (0.3841) GG 191 (0.4312 247 (0.5453) MEGA1 Gen 573 (0.4128 745 (0.424) G G 652(0.4697 883 (0.5026) Gen 573 (0.4128 745 (0.424) G G 652 (0.4697 883(0.5026) hCV12073840 AKT3 (rs14403) LETS Gen 186 (0.4256 153 (0.3392) CC 222 (0.508 274 (0.6075) MEGA1 Gen 510 (0.3783 670 (0.3815) C C 748(0.5549 1001 (0.57) LETS Gen 186 (0.4256 153 (0.3392) C C 222 (0.508 274(0.6075) Gen 186 (0.4256 153 (0.3392) C C 222 (0.508 274 (0.6075) MEGA1Gen 510 (0.3783 670 (0.3815) C C 748 (0.5549 1001 (0.57) Gen 510 (0.3783670 (0.3815) C C 748 (0.5549 1001 (0.57) hCV1678674

KT3 (rs1458023 LETS add 158 (0.3624 126 (0.2812) T T 247 (0.5665 304(0.6786) MEGA1 add 462 (0.3422 540 (0.308) T T 808 (0.5985 1131 (0.6452)LETS Gen 158 (0.3624 126 (0.2812) T T 247 (0.5665 304 (0.6786) Gen 158(0.3624 126 (0.2812) T T 247 (0.5665 304 (0.6786) MEGA1 Gen 462 (0.3422540 (0.308) T T 808 (0.5985 1131 (0.6452) Gen 462 (0.3422 540 (0.308) TT 808 (0.5985 1131 (0.6452) hCV97631

KT3 (rs1538773 LETS add 182 (0.4127 143 (0.3171) T T 224 (0.5079 287(0.6364) MEGA1 add 493 (0.3655 621 (0.3542) T T 754 (0.5589 1043 (0.595)LETS Gen 182 (0.4127 143 (0.3171) T T 224 (0.5079 287 (0.6364) Gen 182(0.4127 143 (0.3171) T T 224 (0.5079 287 (0.6364) MEGA1 Gen 493 (0.3655621 (0.3542) T T 754 (0.5589 1043 (0.595) Gen 493 (0.3655 621 (0.3542) TT 754 (0.5589 1043 (0.595) hCV8688111

KT3 (rs1578275 LETS add 159 (0.3647 125 (0.2803) G G 257 (0.5894 309(0.6928) MEGA1 add 434 (0.3229 541 (0.3097) G G 852 (0.6339 1154(0.6606) LETS Gen 159 (0.3647 125 (0.2803) G G 257 (0.5894 309 (0.6928)Gen 159 (0.3647 125 (0.2803) G G 257 (0.5894 309 (0.6928) MEGA1 Gen 434(0.3229 541 (0.3097) G G 852 (0.6339 1154 (0.6606) Gen 434 (0.3229 541(0.3097) G G 852 (0.6339 1154 (0.6606) hCV15885425

KT3 (rs229075

LETS add 163 (0.3713 126 (0.2788) A A 249 (0.5672 311 (0.6881) MEGA1 add452 (0.3353 528 (0.301) A A 820 (0.6083 1141 (0.6505) LETS Gen 163(0.3713 126 (0.2788) A A 249 (0.5672 311 (0.6881) Gen 163 (0.3713 126(0.2788) A A 249 (0.5672 311 (0.6881) MEGA1 Gen 452 (0.3353 528 (0.301)A A 820 (0.6083 1141 (0.6505) Gen 452 (0.3353 528 (0.301) A A 820(0.6083 1141 (0.6505) hCV1678682 AKT3 (rs320339 LETS add 157 (0.3576 121(0.2701) G G 252 (0.574 309 (0.6897) MEGA1 add 446 (0.3311 532 (0.3035)G G 817 (0.6065 1146 (0.6537) LETS Gen 157 (0.3576 121 (0.2701) G G 252(0.574 309 (0.6897) Gen 157 (0.3576 121 (0.2701) G G 252 (0.574 309(0.6897) MEGA1 Gen 446 (0.3311 532 (0.3035) G G 817 (0.6065 1146(0.6537) Gen 446 (0.3311 532 (0.3035) G G 817 (0.6065 1146 (0.6537)hCV29210363

KT3 (rs6656918 LETS add 179 (0.4087 142 (0.3149) A A 221 (0.5046 287(0.6364) MEGA1 add 490 (0.3632 626 (0.3569) A A 748 (0.5545 1037(0.5912) LETS Gen 179 (0.4087 142 (0.3149) A A 221 (0.5046 287 (0.6364)Gen 179 (0.4087 142 (0.3149) A A 221 (0.5046 287 (0.6364) MEGA1 Gen 490(0.3632 626 (0.3569) A A 748 (0.5545 1037 (0.5912) Gen 490 (0.3632 626(0.3569) A A 748 (0.5545 1037 (0.5912) hCV31523643

KT3 (rs6671475 LETS add 161 (0.3643 127 (0.281) A A 254 (0.5747 310(0.6858) MEGA1 add 453 (0.3356 533 (0.3046) A A 821 (0.6081 1137(0.6497) LETS Gen 161 (0.3643 127 (0.281) A A 254 (0.5747 310 (0.6858)Gen 161 (0.3643 127 (0.281) A A 254 (0.5747 310 (0.6858) MEGA1 Gen 453(0.3356 533 (0.3046) A A 821 (0.6081 1137 (0.6497) Gen 453 (0.3356 533(0.3046) A A 821 (0.6081 1137 (0.6497) hCV26719113

KT3 (rs751734

LETS add 154 (0.3573 109 (0.2477) C C 253 (0.587 315 (0.7159) MEGA1 add431 (0.3207 519 (0.2974) C C 835 (0.6213 1159 (0.6642) LETS Gen 154(0.3573 109 (0.2477) C C 253 (0.587 315 (0.7159) Gen 154 (0.3573 109(0.2477) C C 253 (0.587 315 (0.7159) MEGA1 Gen 431 (0.3207 519 (0.2974)C C 835 (0.6213 1159 (0.6642) Gen 431 (0.3207 519 (0.2974) C C 835(0.6213 1159 (0.6642) hCV26034142

KT3 (rs9428576 LETS add 209 (0.4729 201 (0.4447) T T 121 (0.2738 155(0.3429) MEGA1 rec 634 (0.4703 887 (0.506) T T 396 (0.2938 520 (0.2966)LETS Gen 209 (0.4729 201 (0.4447) T T 121 (0.2738 155 (0.3429) Gen 209(0.4729 201 (0.4447) T T 121 (0.2738 155 (0.3429) MEGA1 Gen 634 (0.4703887 (0.506) T T 396 (0.2938 520 (0.2966) Gen 634 (0.4703 887 (0.506) T T396 (0.2938 520 (0.2966) hCV2303891 POH (rs180169

MEGA1 add 106 (0.0758 189 (0.1076) C C 1288 (0.9213 1565 (0.8907) LETSadd 29 (0.0662 44 (0.098) C C 409 (0.9338 404 (0.8998) LETS Gen 29(0.0662 44 (0.098) C C 409 (0.9338 404 (0.8998) Gen 29 (0.0662 44(0.098) C C 409 (0.9338 404 (0.8998) MEGA1 Gen 106 (0.0758 189 (0.1076)C C 1288 (0.9213 1565 (0.8907) Gen 106 (0.0758 189 (0.1076) C C 1288(0.9213 1565 (0.8907) hCV2456747 orf114 (rs38200 MEGA1 add 641 (0.4595739 (0.4225) G G 542 (0.3885 795 (0.4545) LETS add 210 (0.4751 181(0.3996) G G 177 (0.4005 228 (0.5033) LETS Gen 210 (0.4751 181 (0.3996)G G 177 (0.4005 228 (0.5033) Gen 210 (0.4751 181 (0.3996) G G 177(0.4005 228 (0.5033) MEGA1 Gen 641 (0.4595 739 (0.4225) G G 542 (0.3885795 (0.4545) Gen 641 (0.4595 739 (0.4225) G G 542 (0.3885 795 (0.4545)hCV2403368 QTNF6 (rs2295

LETS rec 145 (0.3281 183 (0.404) G G 272 (0.6154 244 (0.5386) MEGA1 rec477 (0.3427 660 (0.3761) G G 837 (0.6013 989 (0.5635) LETS Gen 145(0.3281 183 (0.404) G G 272 (0.6154 244 (0.5386) Gen 145 (0.3281 183(0.404) G G 272 (0.6154 244 (0.5386) MEGA1 Gen 477 (0.3427 660 (0.3761)G G 837 (0.6013 989 (0.5635) Gen 477 (0.3427 660 (0.3761) G G 837(0.6013 989 (0.5635) hCV7574127 orf167 (rs17371 LETS add 225 (0.509 236(0.521) A A 137 (0.31 120 (0.2649) MEGA1 add 663 (0.4787 847 (0.4834) AA 430 (0.3105 481 (0.2745) LETS Gen 225 (0.509 236 (0.521) A A 137 (0.31120 (0.2649) Gen 225 (0.509 236 (0.521) A A 137 (0.31 120 (0.2649) MEGA1Gen 663 (0.4787 847 (0.4834) A A 430 (0.3105 481 (0.2745) Gen 663(0.4787 847 (0.4834) A A 430 (0.3105 481 (0.2745) hCV25959498 orf46(rs345186 LETS add 48 (0.1086 63 (0.1394) G G 393 (0.8891 383 (0.8473)MEGA1 add 183 (0.1315 262 (0.1493) G G 1203 (0.8642 1476 (0.841) LETSGen 48 (0.1086 63 (0.1394) G G 393 (0.8891 383 (0.8473) Gen 48 (0.108663 (0.1394) G G 393 (0.8891 383 (0.8473) MEGA1 Gen 183 (0.1315 262(0.1493) G G 1203 (0.8642 1476 (0.841) Gen 183 (0.1315 262 (0.1493) G G1203 (0.8642 1476 (0.841) hCV25959466 orf46 (rs354955 MEGA1 add 182(0.1307 263 (0.1503) T T 1203 (0.8642 1469 (0.8394) LETS add 48 (0.108663 (0.1394) T T 393 (0.8891 384 (0.8496) LETS Gen 48 (0.1086 63 (0.1394)T T 393 (0.8891 384 (0.8496) Gen 48 (0.1086 63 (0.1394) T T 393 (0.8891384 (0.8496) MEGA1 Gen 182 (0.1307 263 (0.1503) T T 1203 (0.8642 1469(0.8394) Gen 182 (0.1307 263 (0.1503) T T 1203 (0.8642 1469 (0.8394)hCV25768636

DC36 (rs42791

MEGA1 rec 639 (0.461 821 (0.4678) G G 559 (0.4033 740 (0.4217) LETS rec197 (0.4457 199 (0.4412) G G 177 (0.4005 204 (0.4523) LETS Gen 197(0.4457 199 (0.4412) G G 177 (0.4005 204 (0.4523) Gen 197 (0.4457 199(0.4412) G G 177 (0.4005 204 (0.4523) MEGA1 Gen 639 (0.461 821 (0.4678)G G 559 (0.4033 740 (0.4217) Gen 639 (0.461 821 (0.4678) G G 559 (0.4033740 (0.4217) hCV25991132 CCDC41 ( ) MEGA1 rec 195 (0.1403 311 (0.178) GG 1182 (0.8504 1430 (0.8185) LETS rec 58 (0.1309 78 (0.1722) G G 384(0.8668 370 (0.8168) LETS Gen 58 (0.1309 78 (0.1722) G G 384 (0.8668 370(0.8168) Gen 58 (0.1309 78 (0.1722) G G 384 (0.8668 370 (0.8168) MEGA1Gen 195 (0.1403 311 (0.178) G G 1182 (0.8504 1430 (0.8185) Gen 195(0.1403 311 (0.178) G G 1182 (0.8504 1430 (0.8185) hCV3164397

YA5 (rs100439

LETS rec 93 (0.2109 136 (0.3002) C C 339 (0.7687 309 (0.6821) MEGA1 dom347 (0.2487 408 (0.233) C C 1036 (0.7427 1309 (0.7476) LETS Gen 93(0.2109 136 (0.3002) C C 339 (0.7687 309 (0.6821) Gen 93 (0.2109 136(0.3002) C C 339 (0.7687 309 (0.6821) MEGA1 Gen 347 (0.2487 408 (0.233)C C 1036 (0.7427 1309 (0.7476) Gen 347 (0.2487 408 (0.233) C C 1036(0.7427 1309 (0.7476) hCV3230083 P4V2 (rs100136 MEGA1 Gen 702 (0.5223842 (0.4803) C C 360 (0.2679 582 (0.332) LETS Gen 230 (0.5204 208(0.4622) C C 115 (0.2602 142 (0.3156) LETS Gen 230 (0.5204 208 (0.4622)C C 115 (0.2602 142 (0.3156) Gen 230 (0.5204 208 (0.4622) C C 115(0.2602 142 (0.3156) MEGA1 Gen 702 (0.5223 842 (0.4803) C C 360 (0.2679582 (0.332) Gen 702 (0.5223 842 (0.4803) C C 360 (0.2679 582 (0.332)hCV25990131 P4V2 (rs131462 MEGA1 add 600 (0.4295 805 (0.459) A A 648(0.4639 720 (0.4105) LETS add 208 (0.4717 189 (0.4191) A A 201 (0.4558199 (0.4412) LETS Gen 208 (0.4717 189 (0.4191) A A 201 (0.4558 199(0.4412) Gen 208 (0.4717 189 (0.4191) A A 201 (0.4558 199 (0.4412) MEGA1Gen 600 (0.4295 805 (0.459) A A 648 (0.4639 720 (0.4105) Gen 600 (0.4295805 (0.459) A A 648 (0.4639 720 (0.4105) hCV15968043

P4V2 (rs22924

MEGA1 dom 698 (0.504 839 (0.4811) T T 395 (0.2852 605 (0.3469) LETS dom224 (0.5056 208 (0.4592) T T 122 (0.2754 153 (0.3377) LETS Gen 224(0.5056 208 (0.4592) T T 122 (0.2754 153 (0.3377) Gen 224 (0.5056 208(0.4592) T T 122 (0.2754 153 (0.3377) MEGA1 Gen 698 (0.504 839 (0.4811)T T 395 (0.2852 605 (0.3469) Gen 698 (0.504 839 (0.4811) T T 395 (0.2852605 (0.3469) hCV3230096

P4V2 (rs38171

LETS dom 227 (0.5136 211 (0.4668) C C 120 (0.2715 149 (0.3296) MEGA1 dom680 (0.4892 831 (0.4776) C C 409 (0.2942 600 (0.3448) LETS Gen 227(0.5136 211 (0.4668) C C 120 (0.2715 149 (0.3296) Gen 227 (0.5136 211(0.4668) C C 120 (0.2715 149 (0.3296) MEGA1 Gen 680 (0.4892 831 (0.4776)C C 409 (0.2942 600 (0.3448) Gen 680 (0.4892 831 (0.4776) C C 409(0.2942 600 (0.3448) hCV11786147

P4V2 (rs48626

LETS dom 223 (0.5103 208 (0.4643) G G 120 (0.2746 150 (0.3348) MEGA1 dom665 (0.4941 833 (0.476) G G 403 (0.2994 614 (0.3509) LETS Gen 223(0.5103 208 (0.4643) G G 120 (0.2746 150 (0.3348) Gen 223 (0.5103 208(0.4643) G G 120 (0.2746 150 (0.3348) MEGA1 Gen 665 (0.4941 833 (0.476)G G 403 (0.2994 614 (0.3509) Gen 665 (0.4941 833 (0.476) G G 403 (0.2994614 (0.3509) hCV3230084

P4V2 (rs76829

MEGA1 Gen 670 (0.4989 803 (0.4594) C C 426 (0.3172 657 (0.3759) LETS Gen239 (0.5432 210 (0.4656) C C 126 (0.2864 154 (0.3415) LETS Gen 239(0.5432 210 (0.4656) C C 126 (0.2864 154 (0.3415) Gen 239 (0.5432 210(0.4656) C C 126 (0.2864 154 (0.3415) MEGA1 Gen 670 (0.4989 803 (0.4594)C C 426 (0.3172 657 (0.3759) Gen 670 (0.4989 803 (0.4594) C C 426(0.3172 657 (0.3759) hCV26265231

P4V2 (rs76840

MEGA1 dom 682 (0.5082 853 (0.4897) G G 325 (0.2422 516 (0.2962) LETS dom228 (0.5147 204 (0.4503) G G 99 (0.2235 133 (0.2936) LETS Gen 228(0.5147 204 (0.4503) G G 99 (0.2235 133 (0.2936) Gen 228 (0.5147 204(0.4503) G G 99 (0.2235 133 (0.2936) MEGA1 Gen 682 (0.5082 853 (0.4897)G G 325 (0.2422 516 (0.2962) Gen 682 (0.5082 853 (0.4897) G G 325(0.2422 516 (0.2962) hCV9860072 HX38 (rs105036 LETS Gen 224 (0.5056 195(0.4305) C C 157 (0.3544 196 (0.4327) MEGA1 Gen 632 (0.4586 797 (0.4562)C C 541 (0.3926 730 (0.4179) LETS Gen 224 (0.5056 195 (0.4305) C C 157(0.3544 196 (0.4327) Gen 224 (0.5056 195 (0.4305) C C 157 (0.3544 196(0.4327) MEGA1 Gen 632 (0.4586 797 (0.4562) C C 541 (0.3926 730 (0.4179)Gen 632 (0.4586 797 (0.4562) C C 541 (0.3926 730 (0.4179) hCV2103346

564J102 (rs117 LETS rec 194 (0.4399 230 (0.51) T T 143 (0.3243 144(0.3193) MEGA1 dom 668 (0.4952 834 (0.4752) T T 380 (0.2817 562 (0.3202)LETS Gen 194 (0.4399 230 (0.51) T T 143 (0.3243 144 (0.3193) Gen 194(0.4399 230 (0.51) T T 143 (0.3243 144 (0.3193) MEGA1 Gen 668 (0.4952834 (0.4752) T T 380 (0.2817 562 (0.3202) Gen 668 (0.4952 834 (0.4752) TT 380 (0.2817 562 (0.3202) hCV12086148

564J102 (rs18

LETS rec 138 (0.3129 168 (0.3725) G G 279 (0.6327 258 (0.5721) MEGA1 Gen491 (0.3543 625 (0.358) G G 839 (0.6053 1021 (0.5848) LETS Gen 138(0.3129 168 (0.3725) G G 279 (0.6327 258 (0.5721) Gen 138 (0.3129 168(0.3725) G G 279 (0.6327 258 (0.5721) MEGA1 Gen 491 (0.3543 625 (0.358)G G 839 (0.6053 1021 (0.5848) Gen 491 (0.3543 625 (0.358) G G 839(0.6053 1021 (0.5848) hCV25473516

SP11 (rs22720

LETS Gen 214 (0.4842 224 (0.4956) C C 158 (0.3575 175 (0.3872) MEGA1 Gen641 (0.4615 808 (0.4615) C C 542 (0.3902 734 (0.4192) LETS Gen 214(0.4842 224 (0.4956) C C 158 (0.3575 175 (0.3872) Gen 214 (0.4842 224(0.4956) C C 158 (0.3575 175 (0.3872) MEGA1 Gen 641 (0.4615 808 (0.4615)C C 542 (0.3902 734 (0.4192) Gen 641 (0.4615 808 (0.4615) C C 542(0.3902 734 (0.4192) hCV15871021

BF1 (rs207249

LETS rec 191 (0.4321 238 (0.5254) G G 181 (0.4095 149 (0.3289) MEGA1 dom699 (0.5018 834 (0.4774) G G 526 (0.3776 644 (0.3686) LETS Gen 191(0.4321 238 (0.5254) G G 181 (0.4095 149 (0.3289) Gen 191 (0.4321 238(0.5254) G G 181 (0.4095 149 (0.3289) MEGA1 Gen 699 (0.5018 834 (0.4774)G G 526 (0.3776 644 (0.3686) Gen 699 (0.5018 834 (0.4774) G G 526(0.3776 644 (0.3686) hCV491830

S8L2 (rs30875

LETS add 206 (0.4703 227 (0.5033) T T 158 (0.3607 130 (0.2882) MEGA1 add667 (0.4805 822 (0.47) T T 485 (0.3494 571 (0.3265) LETS Gen 206 (0.4703227 (0.5033) T T 158 (0.3607 130 (0.2882) Gen 206 (0.4703 227 (0.5033) TT 158 (0.3607 130 (0.2882) MEGA1 Gen 667 (0.4805 822 (0.47) T T 485(0.3494 571 (0.3265) Gen 667 (0.4805 822 (0.47) T T 485 (0.3494 571(0.3265) hCV2017876

S8L3 (rs38185

LETS add 202 (0.456 216 (0.4779) G G 145 (0.3273 123 (0.2721) MEGA1 add677 (0.492 888 (0.508) G G 417 (0.3031 466 (0.2666) LETS Gen 202 (0.456216 (0.4779) G G 145 (0.3273 123 (0.2721) Gen 202 (0.456 216 (0.4779) GG 145 (0.3273 123 (0.2721) MEGA1 Gen 677 (0.492 888 (0.508) G G 417(0.3031 466 (0.2666) Gen 677 (0.492 888 (0.508) G G 417 (0.3031 466(0.2666) hCV12066124 F11 (rs2036914 MEGA1 add 682 (0.4903 865 (0.4932) CC 476 (0.3422 482 (0.2748) LETS add 215 (0.4853 216 (0.4768) C C 159(0.3589 138 (0.3046) LETS Gen 215 (0.4853 216 (0.4768) C C 159 (0.3589138 (0.3046) Gen 215 (0.4853 216 (0.4768) C C 159 (0.3589 138 (0.3046)MEGA1 Gen 682 (0.4903 865 (0.4932) C C 476 (0.3422 482 (0.2748) Gen 682(0.4903 865 (0.4932) C C 476 (0.3422 482 (0.2748) hCV16172935 F11(rs2241817 LETS rec 182 (0.4118 220 (0.4867) A A 208 (0.4706 186(0.4115) MEGA1 rec 625 (0.4516 808 (0.4644) A A 620 (0.448 713 (0.4098)LETS Gen 182 (0.4118 220 (0.4867) A A 208 (0.4706 186 (0.4115) Gen 182(0.4118 220 (0.4867) A A 208 (0.4706 186 (0.4115) MEGA1 Gen 625 (0.4516808 (0.4644) A A 620 (0.448 713 (0.4098) Gen 625 (0.4516 808 (0.4644) AA 620 (0.448 713 (0.4098) hCV3230038 F11 (rs2289252 LETS add 204 (0.4626200 (0.4435) C C 130 (0.2948 158 (0.3503) MEGA1 add 689 (0.5115 840(0.48) C C 344 (0.2554 601 (0.3434) LETS Gen 204 (0.4626 200 (0.4435) CC 130 (0.2948 158 (0.3503) Gen 204 (0.4626 200 (0.4435) C C 130 (0.2948158 (0.3503) MEGA1 Gen 689 (0.5115 840 (0.48) C C 344 (0.2554 601(0.3434) Gen 689 (0.5115 840 (0.48) C C 344 (0.2554 601 (0.3434)hCV27474895 F11 (rs3756011 MEGA1 add 692 (0.5018 838 (0.4794) C C 361(0.2618 598 (0.3421) LETS add 208 (0.4695 200 (0.4425) C C 128 (0.2889160 (0.354) LETS Gen 208 (0.4695 200 (0.4425) C C 128 (0.2889 160(0.354) Gen 208 (0.4695 200 (0.4425) C C 128 (0.2889 160 (0.354) MEGA1Gen 692 (0.5018 838 (0.4794) C C 361 (0.2618 598 (0.3421) Gen 692(0.5018 838 (0.4794) C C 361 (0.2618 598 (0.3421) hCV25474413 F11(rs3822057 LETS Gen 214 (0.4831 213 (0.4702) C C 138 (0.3115 124(0.2737) MEGA1 Gen 690 (0.5055 876 (0.4991) C C 406 (0.2974 422 (0.2405)LETS Gen 214 (0.4831 213 (0.4702) C C 138 (0.3115 124 (0.2737) Gen 214(0.4831 213 (0.4702) C C 138 (0.3115 124 (0.2737) MEGA1 Gen 690 (0.5055876 (0.4991) C C 406 (0.2974 422 (0.2405) Gen 690 (0.5055 876 (0.4991) CC 406 (0.2974 422 (0.2405) hCV27490984 F11 (rs3822058 LETS rec 181(0.4095 221 (0.4889) G G 207 (0.4683 185 (0.4093) MEGA1 rec 633 (0.4547816 (0.4671) G G 624 (0.4483 712 (0.4076) LETS Gen 181 (0.4095 221(0.4889) G G 207 (0.4683 185 (0.4093) Gen 181 (0.4095 221 (0.4889) G G207 (0.4683 185 (0.4093) MEGA1 Gen 633 (0.4547 816 (0.4671) G G 624(0.4483 712 (0.4076) Gen 633 (0.4547 816 (0.4671) G G 624 (0.4483 712(0.4076) hCV25474414 F11 (rs4253399 MEGA1 add 658 (0.4892 831 (0.4735) TT 409 (0.3041 660 (0.3761) LETS add 205 (0.4649 192 (0.4257) T T 142(0.322 179 (0.3969) LETS Gen 205 (0.4649 192 (0.4257) G T 142 (0.322 179(0.3969) Gen 205 (0.4649 192 (0.4257) T T 142 (0.322 179 (0.3969) MEGA1Gen 658 (0.4892 831 (0.4735) T T 409 (0.3041 660 (0.3761) Gen 658(0.4892 831 (0.4735) T T 409 (0.3041 660 (0.3761) hCV26038139 F11(rs4253405 MEGA1 Gen 643 (0.4619 814 (0.4646) A A 607 (0.4361 689(0.3933) LETS Gen 179 (0.4059 225 (0.4978) A A 199 (0.4512 175 (0.3872)LETS Gen 179 (0.4059 225 (0.4978) A A 199 (0.4512 175 (0.3872) Gen 179(0.4059 225 (0.4978) A A 199 (0.4512 175 (0.3872) MEGA1 Gen 643 (0.4619814 (0.4646) A A 607 (0.4361 689 (0.3933) Gen 643 (0.4619 814 (0.4646) AA 607 (0.4361 689 (0.3933) hCV3230119 F11 (rs4253430 LETS rec 183 (0.415222 (0.4912) G G 206 (0.4671 182 (0.4027) MEGA1 rec 631 (0.454 812(0.4635) G G 624 (0.4489 722 (0.4121) LETS Gen 183 (0.415 222 (0.4912) GG 206 (0.4671 182 (0.4027) Gen 183 (0.415 222 (0.4912) G G 206 (0.4671182 (0.4027) MEGA1 Gen 631 (0.454 812 (0.4635) G G 624 (0.4489 722(0.4121) Gen 631 (0.454 812 (0.4635) G G 624 (0.4489 722 (0.4121)hCV8241630 F11 (rs925451) MEGA1 add 666 (0.4904 816 (0.4663) G G 403(0.2968 662 (0.3783) LETS add 212 (0.4807 194 (0.4292) G G 134 (0.3039171 (0.3783) LETS Gen 212 (0.4807 194 (0.4292) G G 134 (0.3039 171(0.3783) Gen 212 (0.4807 194 (0.4292) G G 134 (0.3039 171 (0.3783) MEGA1Gen 666 (0.4904 816 (0.4663) G G 403 (0.2968 662 (0.3783) Gen 666(0.4904 816 (0.4663) G G 403 (0.2968 662 (0.3783) hCV8726802 F2(rs1799963) MEGA1 add 80 (0.0579 37 (0.0211) G G 1301 (0.9421 1716(0.9789) LETS add 28 (0.0633 10 (0.0221) G G 414 (0.9367 442 (0.9779)LETS Gen 28 (0.0633 10 (0.0221) A A 414 (0.9367 442 (0.9779) MEGA1 Gen80 (0.0579 37 (0.0211) G G 1301 (0.9421 1716 (0.9789) hCV27480803 F5(rs3766103) MEGA1 add 660 (0.4755 840 (0.4805) T T 382 (0.2752 557(0.3186) LETS add 216 (0.4898 222 (0.4901) T T 129 (0.2925 158 (0.3488)LETS Gen 216 (0.4898 222 (0.4901) T T 129 (0.2925 158 (0.3488) Gen 216(0.4898 222 (0.4901) T T 129 (0.2925 158 (0.3488) MEGA1 Gen 660 (0.4755840 (0.4805) T T 382 (0.2752 557 (0.3186) Gen 660 (0.4755 840 (0.4805) TT 382 (0.2752 557 (0.3186) hCV8919444 F5 (rs4524) MEGA1 add 440 (0.317680 (0.3883) T T 872 (0.6282 964 (0.5505) LETS add 130 (0.2935 169(0.3739) T T 289 (0.6524 251 (0.5553) LETS Gen 130 (0.2935 169 (0.3739)T T 289 (0.6524 251 (0.5553) Gen 130 (0.2935 169 (0.3739) T T 289(0.6524 251 (0.5553) MEGA1 Gen 440 (0.317 680 (0.3883) T T 872 (0.6282964 (0.5505) Gen 440 (0.317 680 (0.3883) T T 872 (0.6282 964 (0.5505)hCV8919442 F5 (rs4525) MEGA1 add 431 (0.3148 685 (0.3899) T T 864(0.6311 965 (0.5492) LETS add 128 (0.2909 168 (0.3733) T T 287 (0.6523251 (0.5578) LETS Gen 128 (0.2909 168 (0.3733) T T 287 (0.6523 251(0.5578) Gen 128 (0.2909 168 (0.3733) T T 287 (0.6523 251 (0.5578) MEGA1Gen 431 (0.3148 685 (0.3899) T T 864 (0.6311 965 (0.5492) Gen 431(0.3148 685 (0.3899) T T 864 (0.6311 965 (0.5492) hCV8919451 F5 (rs6016)MEGA1 add 430 (0.31 679 (0.3869) G G 879 (0.6337 968 (0.5516) LETS add130 (0.2948 170 (0.3778) G G 287 (0.6508 249 (0.5533) LETS Gen 130(0.2948 170 (0.3778) G G 287 (0.6508 249 (0.5533) Gen 130 (0.2948 170(0.3778) G G 287 (0.6508 249 (0.5533) MEGA1 Gen 430 (0.31 679 (0.3869) GG 879 (0.6337 968 (0.5516) Gen 430 (0.31 679 (0.3869) G G 879 (0.6337968 (0.5516) hCV2288095 F9 (rs378815) LETS Gen 111 (0.2517 120 (0.2667)C C 250 (0.5669 223 (0.4956) MEGA1 Gen 331 (0.2381 378 (0.2161) C C 753(0.5417 940 (0.5374) LETS Gen 111 (0.2517 120 (0.2667) C C 250 (0.5669223 (0.4956) Gen 111 (0.2517 120 (0.2667) C C 250 (0.5669 223 (0.4956)MEGA1 Gen 331 (0.2381 378 (0.2161) C C 753 (0.5417 940 (0.5374) Gen 331(0.2381 378 (0.2161) C C 753 (0.5417 940 (0.5374) hCV596326 F9(rs398101) LETS rec 91 (0.2068 120 (0.2655) A A 274 (0.6227 240 (0.531)MEGA1 Gen 310 (0.224 350 (0.1998) A A 817 (0.5903 1021 (0.5828) LETS Gen91 (0.2068 120 (0.2655) A A 274 (0.6227 240 (0.531) Gen 91 (0.2068 120(0.2655) A A 274 (0.6227 240 (0.531) MEGA1 Gen 310 (0.224 350 (0.1998) AA 817 (0.5903 1021 (0.5828) Gen 310 (0.224 350 (0.1998) A A 817 (0.59031021 (0.5828) hCV596330 F9 (rs422187) LETS add 103 (0.2336 120 (0.2667)A A 268 (0.6077 243 (0.54) MEGA1 add 314 (0.2274 361 (0.2062) A A 824(0.5967 1014 (0.5791) LETS Gen 103 (0.2336 120 (0.2667) A A 268 (0.6077243 (0.54) Gen 103 (0.2336 120 (0.2667) A A 268 (0.6077 243 (0.54) MEGA1Gen 314 (0.2274 361 (0.2062) A A 824 (0.5967 1014 (0.5791) Gen 314(0.2274 361 (0.2062) A A 824 (0.5967 1014 (0.5791) hCV596331 F9 (rs6048)LETS rec 99 (0.2235 122 (0.2693) A A 274 (0.6185 244 (0.5386) MEGA1 dom295 (0.215 347 (0.1994) A A 844 (0.6152 1037 (0.596) LETS Gen 99 (0.2235122 (0.2693) A A 274 (0.6185 244 (0.5386) Gen 99 (0.2235 122 (0.2693) AA 274 (0.6185 244 (0.5386) MEGA1 Gen 295 (0.215 347 (0.1994) A A 844(0.6152 1037 (0.596) Gen 295 (0.215 347 (0.1994) A A 844 (0.6152 1037(0.596) hCV2892877 FGA (rs6050) LETS add 249 (0.5621 226 (0.4989) T T194 (0.4379 227 (0.5011) MEGA1 add 807 (0.5814 859 (0.4914) T T 581(0.4186 889 (0.5086) LETS Gen 249 (0.5621 226 (0.4989) T T 194 (0.4379227 (0.5011) MEGA1 Gen 807 (0.5814 859 (0.4914) T T 581 (0.4186 889(0.5086) hCV11503469

GG (rs2066854 MEGA1 add 624 (0.4486 687 (0.3917) T T 593 (0.4263 928(0.5291) LETS add 183 (0.4207 187 (0.424) T T 198 (0.4552 232 (0.5261)LETS Gen 183 (0.4207 187 (0.424) T T 198 (0.4552 232 (0.5261) Gen 183(0.4207 187 (0.424) T T 198 (0.4552 232 (0.5261) MEGA1 Gen 624 (0.4486687 (0.3917) T T 593 (0.4263 928 (0.5291) Gen 624 (0.4486 687 (0.3917) TT 593 (0.4263 928 (0.5291) hCV11503414

GG (rs2066865 MEGA1 add 608 (0.451 692 (0.3941) G G 574 (0.4258 928(0.5285) LETS add 186 (0.4256 188 (0.4206) G G 195 (0.4462 235 (0.5257)LETS Gen 186 (0.4256 188 (0.4206) G G 195 (0.4462 235 (0.5257) Gen 186(0.4256 188 (0.4206) G G 195 (0.4462 235 (0.5257) MEGA1 Gen 608 (0.451692 (0.3941) G G 574 (0.4258 928 (0.5285) Gen 608 (0.451 692 (0.3941) GG 574 (0.4258 928 (0.5285) hCV30505633 GNG12 (rs753053 LETS add 68(0.1538 52 (0.1148) C C 369 (0.8348 400 (0.883) MEGA1 add 206 (0.1486229 (0.1304) C C 1164 (0.8398 1515 (0.8628) LETS Gen 68 (0.1538 52(0.1148) C C 369 (0.8348 400 (0.883) Gen 68 (0.1538 52 (0.1148) C C 369(0.8348 400 (0.883) MEGA1 Gen 206 (0.1486 229 (0.1304) C C 1164 (0.83981515 (0.8628) Gen 206 (0.1486 229 (0.1304) C C 1164 (0.8398 1515(0.8628) hCV8717873 GP6 (rs1613662 MEGA1 add 368 (0.2651 553 (0.3162) AA 975 (0.7024 1135 (0.6489) LETS add 117 (0.2641 143 (0.3157) A A 316(0.7133 291 (0.6424) LETS Gen 117 (0.2641 143 (0.3157) A A 316 (0.7133291 (0.6424) Gen 117 (0.2641 143 (0.3157) A A 316 (0.7133 291 (0.6424)MEGA1 Gen 368 (0.2651 553 (0.3162) A A 975 (0.7024 1135 (0.6489) Gen 368(0.2651 553 (0.3162) A A 975 (0.7024 1135 (0.6489) hCV1376342 GP6(rs1654416 LETS Gen 130 (0.2935 142 (0.3135) T T 298 (0.6727 285(0.6291) MEGA1 rec 393 (0.2875 580 (0.3307) T T 925 (0.6767 1108(0.6317) LETS Gen 130 (0.2935 142 (0.3135) T T 298 (0.6727 285 (0.6291)Gen 130 (0.2935 142 (0.3135) T T 298 (0.6727 285 (0.6291) MEGA1 Gen 393(0.2875 580 (0.3307) T T 925 (0.6767 1108 (0.6317) Gen 393 (0.2875 580(0.3307) T T 925 (0.6767 1108 (0.6317) hCV8717893 GP6 (rs1671192 LETSGen 130 (0.2941 142 (0.3135) G G 297 (0.6719 285 (0.6291) MEGA1 rec 393(0.2831 584 (0.3326) G G 944 (0.6801 1108 (0.631) LETS Gen 130 (0.2941142 (0.3135) G G 297 (0.6719 285 (0.6291) Gen 130 (0.2941 142 (0.3135) GG 297 (0.6719 285 (0.6291) MEGA1 Gen 393 (0.2831 584 (0.3326) G G 944(0.6801 1108 (0.631) Gen 393 (0.2831 584 (0.3326) G G 944 (0.6801 1108(0.631) hCV2575036 RB10 (rs344327 LETS add 8 (0.0181 24 (0.053) A A 433(0.9819 429 (0.947) MEGA1 add 68 (0.0498 61 (0.0348) A A 1297 (0.94951692 (0.9652) LETS Gen 8 (0.0181 24 (0.053) A A 433 (0.9819 429 (0.947)MEGA1 Gen 68 (0.0498 61 (0.0348) A A 1297 (0.9495 1692 (0.9652) Gen 68(0.0498 61 (0.0348) A A 1297 (0.9495 1692 (0.9652) hCV2699725 CY1B2(rs11841 LETS Gen 33 (0.0755 19 (0.0424) G G 401 (0.9176 428 (0.9554)MEGA1 Gen 102 (0.0731 98 (0.0558) C C 1290 (0.9241 1654 (0.9414) LETSGen 33 (0.0755 19 (0.0424) G G 401 (0.9176 428 (0.9554) Gen 33 (0.075519 (0.0424) G G 401 (0.9176 428 (0.9554) MEGA1 Gen 102 (0.0731 98(0.0558) C C 1290 (0.9241 1654 (0.9414) Gen 102 (0.0731 98 (0.0558) C C1290 (0.9241 1654 (0.9414) hCV25995678 hCV25995678 LETS add 61 (0.138 85(0.1881) T T 377 (0.8529 359 (0.7942) MEGA1 dom 222 (0.1594 277 (0.1586)T T 1166 (0.837 1452 (0.8316) LETS Gen 61 (0.138 85 (0.1881) T T 377(0.8529 359 (0.7942) Gen 61 (0.138 85 (0.1881) T T 377 (0.8529 359(0.7942) MEGA1 Gen 222 (0.1594 277 (0.1586) T T 1166 (0.837 1452(0.8316) Gen 222 (0.1594 277 (0.1586) T T 1166 (0.837 1452 (0.8316)hCV25996277 hCV25996277 LETS add 63 (0.1422 86 (0.1898) A A 376 (0.8488359 (0.7925) MEGA1 Gen 217 (0.157 277 (0.158) A A 1160 (0.8394 1456(0.8306) LETS Gen 63 (0.1422 86 (0.1898) A A 376 (0.8488 359 (0.7925)Gen 63 (0.1422 86 (0.1898) A A 376 (0.8488 359 (0.7925) MEGA1 Gen 217(0.157 277 (0.158) A A 1160 (0.8394 1456 (0.8306) Gen 217 (0.157 277(0.158) A A 1160 (0.8394 1456 (0.8306) hCV31199195 TD10 (rs108502 LETSdom 142 (0.3205 111 (0.245) A A 289 (0.6524 328 (0.7241) MEGA1 dom 423(0.3048 486 (0.2772) A A 913 (0.6578 1215 (0.6931) LETS Gen 142 (0.3205111 (0.245) A A 289 (0.6524 328 (0.7241) Gen 142 (0.3205 111 (0.245) A A289 (0.6524 328 (0.7241) MEGA1 Gen 423 (0.3048 486 (0.2772) A A 913(0.6578 1215 (0.6931) Gen 423 (0.3048 486 (0.2772) A A 913 (0.6578 1215(0.6931) hCV27502514

LF3 (rs379653

MEGA1 dom 410 (0.2962 465 (0.2654) G G 930 (0.672 1242 (0.7089) LETS dom146 (0.3296 122 (0.2693) G G 280 (0.6321 316 (0.6976) LETS Gen 146(0.3296 122 (0.2693) G G 280 (0.6321 316 (0.6976) Gen 146 (0.3296 122(0.2693) G G 280 (0.6321 316 (0.6976) MEGA1 Gen 410 (0.2962 465 (0.2654)G G 930 (0.672 1242 (0.7089) Gen 410 (0.2962 465 (0.2654) G G 930 (0.6721242 (0.7089) hCV11786258 _KB1 (rs425330 LETS Gen 226 (0.5136 208(0.4622) G G 131 (0.2977 159 (0.3533) MEGA1 Gen 686 (0.4932 815 (0.4649)G G 434 (0.312 656 (0.3742) LETS Gen 226 (0.5136 208 (0.4622) G G 131(0.2977 159 (0.3533) Gen 226 (0.5136 208 (0.4622) G G 131 (0.2977 159(0.3533) MEGA1 Gen 686 (0.4932 815 (0.4649) G G 434 (0.312 656 (0.3742)Gen 686 (0.4932 815 (0.4649) G G 434 (0.312 656 (0.3742) hCV540410 ASP1(rs60952

LETS Gen 59 (0.1335 42 (0.0927) T T 381 (0.862 407 (0.8985) MEGA1 Gen178 (0.1276 216 (0.123) T T 1202 (0.8616 1535 (0.8741) LETS Gen 59(0.1335 42 (0.0927) T T 381 (0.862 407 (0.8985) Gen 59 (0.1335 42(0.0927) T T 381 (0.862 407 (0.8985) MEGA1 Gen 178 (0.1276 216 (0.123) TT 1202 (0.8616 1535 (0.8741) Gen 178 (0.1276 216 (0.123) T T 1202(0.8616 1535 (0.8741) hDV70662128 129656 (rs1704

LETS add 35 (0.0792 22 (0.0486) G G 407 (0.9208 431 (0.9514) MEGA1 add105 (0.0758 83 (0.0473) G G 1275 (0.9206 1667 (0.9504) LETS Gen 35(0.0792 22 (0.0486) G G 407 (0.9208 431 (0.9514) MEGA1 Gen 105 (0.075883 (0.0473) G G 1275 (0.9206 1667 (0.9504) Gen 105 (0.0758 83 (0.0473) GG 1275 (0.9206 1667 (0.9504) hCV11541681 200420 (rs2001 MEGA1 add 662(0.4756 815 (0.4644) G G 502 (0.3606 697 (0.3972) LETS add 220 (0.4966228 (0.5033) G G 142 (0.3205 165 (0.3642) LETS Gen 220 (0.4966 228(0.5033) G G 142 (0.3205 165 (0.3642) Gen 220 (0.4966 228 (0.5033) G G142 (0.3205 165 (0.3642) MEGA1 Gen 662 (0.4756 815 (0.4644) G G 502(0.3606 697 (0.3972) Gen 662 (0.4756 815 (0.4644) G G 502 (0.3606 697(0.3972) hCV2706410 387646 (rs7896 LETS Gen 175 (0.3959 146 (0.323) T T234 (0.5294 276 (0.6106) MEGA1 Gen 535 (0.3914 622 (0.354) T T 746(0.5457 1014 (0.5771) LETS Gen 175 (0.3959 146 (0.323) T T 234 (0.5294276 (0.6106) Gen 175 (0.3959 146 (0.323) T T 234 (0.5294 276 (0.6106)MEGA1 Gen 535 (0.3914 622 (0.354) T T 746 (0.5457 1014 (0.5771) Gen 535(0.3914 622 (0.354) T T 746 (0.5457 1014 (0.5771) hCV1547677 646030(rs6505 LETS add 20 (0.0452 8 (0.0179) A A 422 (0.9548 439 (0.9821)MEGA1 add 39 (0.0286 47 (0.0268) A A 1312 (0.9605 1702 (0.9698) LETS Gen20 (0.0452 8 (0.0179) A A 422 (0.9548 439 (0.9821) MEGA1 Gen 39 (0.028647 (0.0268) A A 1312 (0.9605 1702 (0.9698) Gen 39 (0.0286 47 (0.0268) AA 1312 (0.9605 1702 (0.9698) hCV8827309 728221 (rs1110 LETS add 107(0.2437 83 (0.1836) C C 321 (0.7312 364 (0.8053) MEGA1 add 339 (0.2453368 (0.2131) C C 1022 (0.7395 1335 (0.773) LETS Gen 107 (0.2437 83(0.1836) C C 321 (0.7312 364 (0.8053) Gen 107 (0.2437 83 (0.1836) C C321 (0.7312 364 (0.8053) MEGA1 Gen 339 (0.2453 368 (0.2131) C C 1022(0.7395 1335 (0.773) Gen 339 (0.2453 368 (0.2131) C C 1022 (0.7395 1335(0.773) hCV2103392 728284 (rs1250

LETS dom 197 (0.4457 192 (0.4248) C C 196 (0.4434 193 (0.427) MEGA1 dom622 (0.4625 827 (0.4718) C C 570 (0.4238 674 (0.3845) LETS Gen 197(0.4457 192 (0.4248) C C 196 (0.4434 193 (0.427) Gen 197 (0.4457 192(0.4248) C C 196 (0.4434 193 (0.427) MEGA1 Gen 622 (0.4625 827 (0.4718)C C 570 (0.4238 674 (0.3845) Gen 622 (0.4625 827 (0.4718) C C 570(0.4238 674 (0.3845) hCV3230136 728284 (rs1311

MEGA1 rec 530 (0.3813 716 (0.4091) G G 785 (0.5647 904 (0.5166) LETS rec146 (0.3311 183 (0.4049) G G 264 (0.5986 238 (0.5265) LETS Gen 146(0.3311 183 (0.4049) G G 264 (0.5986 238 (0.5265) Gen 146 (0.3311 183(0.4049) G G 264 (0.5986 238 (0.5265) MEGA1 Gen 530 (0.3813 716 (0.4091)G G 785 (0.5647 904 (0.5166) Gen 530 (0.3813 716 (0.4091) G G 785(0.5647 904 (0.5166) hCV3230131 728284 (rs1313

LETS rec 149 (0.3371 182 (0.4035) T T 262 (0.5928 238 (0.5277) MEGA1 rec528 (0.3799 719 (0.4104) T T 788 (0.5669 899 (0.5131) LETS Gen 149(0.3371 182 (0.4035) T T 262 (0.5928 238 (0.5277) Gen 149 (0.3371 182(0.4035) T T 262 (0.5928 238 (0.5277) MEGA1 Gen 528 (0.3799 719 (0.4104)T T 788 (0.5669 899 (0.5131) Gen 528 (0.3799 719 (0.4104) T T 788(0.5669 899 (0.5131) hCV29821005 728284 (rs6552 LETS Gen 170 (0.3864 147(0.3267) C C 250 (0.5682 284 (0.6311) MEGA1 Gen 463 (0.3442 528 (0.3009)C C 820 (0.6097 1150 (0.6553) LETS Gen 170 (0.3864 147 (0.3267) C C 250(0.5682 284 (0.6311) Gen 170 (0.3864 147 (0.3267) C C 250 (0.5682 284(0.6311) MEGA1 Gen 463 (0.3442 528 (0.3009) C C 820 (0.6097 1150(0.6553) Gen 463 (0.3442 528 (0.3009) C C 820 (0.6097 1150 (0.6553)hCV32209621 728284 (rs6552 LETS Gen 226 (0.5125 202 (0.4499) A A 124(0.2812 134 (0.2984) MEGA1 Gen 669 (0.4959 854 (0.4866) A A 375 (0.278451 (0.257) LETS Gen 226 (0.5125 202 (0.4499) A A 124 (0.2812 134(0.2984) Gen 226 (0.5125 202 (0.4499) A A 124 (0.2812 134 (0.2984) MEGA1Gen 669 (0.4959 854 (0.4866) A A 375 (0.278 451 (0.257) Gen 669 (0.4959854 (0.4866) A A 375 (0.278 451 (0.257) hCV32209620 728284 (rs6552 LETSdom 166 (0.3773 145 (0.3215) T T 251 (0.5705 285 (0.6319) MEGA1 dom 461(0.344 527 (0.3022) T T 817 (0.6097 1141 (0.6542) LETS Gen 166 (0.3773145 (0.3215) T T 251 (0.5705 285 (0.6319) Gen 166 (0.3773 145 (0.3215) TT 251 (0.5705 285 (0.6319) MEGA1 Gen 461 (0.344 527 (0.3022) T T 817(0.6097 1141 (0.6542) Gen 461 (0.344 527 (0.3022) T T 817 (0.6097 1141(0.6542) hCV916107

729138 (rs670

LETS add 185 (0.4186 200 (0.4415) C C 216 (0.4887 192 (0.4238) MEGA1 add620 (0.4457 773 (0.442) C C 622 (0.4472 738 (0.422) LETS Gen 185 (0.4186200 (0.4415) C C 216 (0.4887 192 (0.4238) Gen 185 (0.4186 200 (0.4415) CC 216 (0.4887 192 (0.4238) MEGA1 Gen 620 (0.4457 773 (0.442) C C 622(0.4472 738 (0.422) Gen 620 (0.4457 773 (0.442) C C 622 (0.4472 738(0.422) hCV30922162 729672 (rs4334 LETS add 201 (0.4548 202 (0.4459) C C191 (0.4321 222 (0.4901) MEGA1 add 601 (0.433 748 (0.4262) C C 655(0.4719 874 (0.498) LETS Gen 201 (0.4548 202 (0.4459) C C 191 (0.4321222 (0.4901) Gen 201 (0.4548 202 (0.4459) C C 191 (0.4321 222 (0.4901)MEGA1 Gen 601 (0.433 748 (0.4262) C C 655 (0.4719 874 (0.498) Gen 601(0.433 748 (0.4262) C C 655 (0.4719 874 (0.498) hCV7504118

729672 (rs967

MEGA1 add 595 (0.4293 734 (0.418) A A 668 (0.482 902 (0.5137) LETS add200 (0.4525 195 (0.4305) A A 198 (0.448 229 (0.5055) LETS Gen 200(0.4525 195 (0.4305) A A 198 (0.448 229 (0.5055) Gen 200 (0.4525 195(0.4305) A A 198 (0.448 229 (0.5055) MEGA1 Gen 595 (0.4293 734 (0.418) AA 668 (0.482 902 (0.5137) Gen 595 (0.4293 734 (0.418) A A 668 (0.482 902(0.5137) hCV11633415

730144 (rs4262 MEGA1 add 156 (0.1124 258 (0.147) T T 1226 (0.8833 1486(0.8467) LETS add 51 (0.1151 67 (0.1482) T T 392 (0.8849 381 (0.8429)LETS Gen 51 (0.1151 67 (0.1482) T T 392 (0.8849 381 (0.8429) Gen 51(0.1151 67 (0.1482) T T 392 (0.8849 381 (0.8429) MEGA1 Gen 156 (0.1124258 (0.147) T T 1226 (0.8833 1486 (0.8467) Gen 156 (0.1124 258 (0.147) TT 1226 (0.8833 1486 (0.8467) hCV2494846 JZP1 (rs376540 MEGA1 rec 386(0.2775 491 (0.2801) T T 950 (0.683 1217 (0.6942) LETS rec 119 (0.2692108 (0.2389) T T 302 (0.6833 334 (0.7389) LETS Gen 119 (0.2692 108(0.2389) T T 302 (0.6833 334 (0.7389) Gen 119 (0.2692 108 (0.2389) T T302 (0.6833 334 (0.7389) MEGA1 Gen 386 (0.2775 491 (0.2801) T T 950(0.683 1217 (0.6942) Gen 386 (0.2775 491 (0.2801) T T 950 (0.683 1217(0.6942) hCV25752810 IDN1 (rs470755

MEGA1 add 67 (0.049 59 (0.0336) A A 1294 (0.9459 1693 (0.9641) LETS add22 (0.0498 11 (0.0244) A A 417 (0.9434 439 (0.9734) LETS Gen 22 (0.049811 (0.0244) A A 417 (0.9434 439 (0.9734) Gen 22 (0.0498 11 (0.0244) A A417 (0.9434 439 (0.9734) MEGA1 Gen 67 (0.049 59 (0.0336) A A 1294(0.9459 1693 (0.9641) Gen 67 (0.049 59 (0.0336) A A 1294 (0.9459 1693(0.9641) hCV16170613 MET (rs2237712 MEGA1 add 113 (0.081 108 (0.0615) AA 1279 (0.9168 1647 (0.9379) LETS add 37 (0.0837 27 (0.0597) A A 401(0.9072 425 (0.9403) LETS Gen 37 (0.0837 27 (0.0597) A A 401 (0.9072 425(0.9403) Gen 37 (0.0837 27 (0.0597) A A 401 (0.9072 425 (0.9403) MEGA1Gen 113 (0.081 108 (0.0615) A A 1279 (0.9168 1647 (0.9379) Gen 113(0.081 108 (0.0615) A A 1279 (0.9168 1647 (0.9379) hCV11726971

FIA (rs2065841 LETS Gen 126 (0.2844 117 (0.2583) A A 294 (0.6637 326(0.7196) MEGA1 Gen 465 (0.3362 526 (0.2999) A A 867 (0.6269 1153(0.6574) LETS Gen 126 (0.2844 117 (0.2583) A A 294 (0.6637 326 (0.7196)Gen 126 (0.2844 117 (0.2583) A A 294 (0.6637 326 (0.7196) MEGA1 Gen 465(0.3362 526 (0.2999) A A 867 (0.6269 1153 (0.6574) Gen 465 (0.3362 526(0.2999) A A 867 (0.6269 1153 (0.6574) hCV30747430 R1I2 (rs1171221 MEGA1add 424 (0.3141 520 (0.2963) C C 850 (0.6296 1170 (0.6667) LETS add 122(0.2773 115 (0.255) C C 292 (0.6636 325 (0.7206) LETS Gen 122 (0.2773115 (0.255) C C 292 (0.6636 325 (0.7206) Gen 122 (0.2773 115 (0.255) C C292 (0.6636 325 (0.7206) MEGA1 Gen 424 (0.3141 520 (0.2963) C C 850(0.6296 1170 (0.6667) Gen 424 (0.3141 520 (0.2963) C C 850 (0.6296 1170(0.6667) hCV263841 R1I2 (rs152312 LETS add 190 (0.4358 194 (0.4379) A A158 (0.3624 200 (0.4515) MEGA1 add 685 (0.49 851 (0.4843) A A 463(0.3312 645 (0.3671) LETS Gen 190 (0.4358 194 (0.4379) A A 158 (0.3624200 (0.4515) Gen 190 (0.4358 194 (0.4379) A A 158 (0.3624 200 (0.4515)MEGA1 Gen 685 (0.49 851 (0.4843) A A 463 (0.3312 645 (0.3671) Gen 685(0.49 851 (0.4843) A A 463 (0.3312 645 (0.3671) hCV4041 NR3C1 (rs6190)MEGA1 dom 96 (0.0701 92 (0.0524) C C 1269 (0.927 1662 (0.947) LETS dom41 (0.0928 26 (0.0575) C C 400 (0.905 425(0.9403) LETS Gen 41 (0.0928 26(0.0575) C C 400 (0.905 425 (0.9403) Gen 41 (0.0928 26 (0.0575) C C 400(0.905 425 (0.9403) MEGA1 Gen 96 (0.0701 92 (0.0524) C C 1269 (0.9271662 (0.947) Gen 96 (0.0701 92 (0.0524) C C 1269 (0.927 1662 (0.947)hCV2915511

BSL1 (rs62753

LETS Gen 40 (0.0905 22 (0.0487) T T 399 (0.9027 429 (0.9491) MEGA1 Gen92 (0.0661 126 (0.0718) T T 1287 (0.9246 1624 (0.9254) LETS Gen 40(0.0905 22 (0.0487) T T 399 (0.9027 429 (0.9491) Gen 40 (0.0905 22(0.0487) T T 399 (0.9027 429 (0.9491) MEGA1 Gen 92 (0.0661 126 (0.0718)T T 1287 (0.9246 1624 (0.9254) Gen 92 (0.0661 126 (0.0718) T T 1287(0.9246 1624 (0.9254) hCV16177220

DZ1 (rs226691

MEGA1 add 212 (0.1524 308 (0.1756) C C 1054 (0.7577 1232 (0.7024) LETSadd 72 (0.1625 85 (0.1876) C C 336 (0.7585 314 (0.6932) LETS Gen 72(0.1625 85 (0.1876) C C 336 (0.7585 314 (0.6932) Gen 72 (0.1625 85(0.1876) C C 336 (0.7585 314 (0.6932) MEGA1 Gen 212 (0.1524 308 (0.1756)C C 1054 (0.7577 1232 (0.7024) Gen 212 (0.1524 308 (0.1756) C C 1054(0.7577 1232 (0.7024) hCV7584272 R1B1 (rs153692 LETS Gen 187 (0.424 166(0.3673) G G 228 (0.517 262 (0.5796) MEGA1 dom 545 (0.3987 645 (0.3675)G G 739 (0.5406 1012 (0.5766) LETS Gen 187 (0.424 166 (0.3673) G G 228(0.517 262 (0.5796) Gen 187 (0.424 166 (0.3673) G G 228 (0.517 262(0.5796) MEGA1 Gen 545 (0.3987 645 (0.3675) G G 739 (0.5406 1012(0.5766) Gen 545 (0.3987 645 (0.3675) G G 739 (0.5406 1012 (0.5766)hCV9327878 R7G1 (rs221765 MEGA1 add 600 (0.4386 733 (0.4174) C C 588(0.4298 833 (0.4744) LETS add 191 (0.4341 185 (0.4129) C C 188 (0.4273218 (0.4866) LETS Gen 191 (0.4341 185 (0.4129) C C 188 (0.4273 218(0.4866) Gen 191 (0.4341 185 (0.4129) C C 188 (0.4273 218 (0.4866) MEGA1Gen 600 (0.4386 733 (0.4174) C C 588 (0.4298 833 (0.4744) Gen 600(0.4386 733 (0.4174) C C 588 (0.4298 833 (0.4744) hCV15990789 TOG(rs235546 MEGA1 rec 600 (0.4402 857 (0.4889) G G 543 (0.3984 617 (0.352)LETS rec 205 (0.4638 241 (0.5344) G G 162 (0.3665 130 (0.2882) LETS Gen205 (0.4638 241 (0.5344) G G 162 (0.3665 130 (0.2882) Gen 205 (0.4638241 (0.5344) G G 162 (0.3665 130 (0.2882) MEGA1 Gen 600 (0.4402 857(0.4889) G G 543 (0.3984 617 (0.352) Gen 600 (0.4402 857 (0.4889) G G543 (0.3984 617 (0.352) hCV8361354 ANX1 (rs113880 LETS Gen 203 (0.4582223 (0.4923) C C 192 (0.4334 160 (0.3532) MEGA1 Gen 636 (0.4582 875(0.4994) C C 545 (0.3927 650 (0.371) LETS Gen 203 (0.4582 223 (0.4923) CC 192 (0.4334 160 (0.3532) Gen 203 (0.4582 223 (0.4923) C C 192 (0.4334160 (0.3532) MEGA1 Gen 636 (0.4582 875 (0.4994) C C 545 (0.3927 650(0.371) Gen 636 (0.4582 875 (0.4994) C C 545 (0.3927 650 (0.371)hCV30500334 ACTR3 (rs61286 LETS add 195 (0.4402 230 (0.5077) G G 189(0.4266 149 (0.3289) MEGA1 add 630 (0.4626 823 (0.4689) G G 547 (0.4016647 (0.3687) LETS Gen 195 (0.4402 230 (0.5077) G G 189 (0.4266 149(0.3289) Gen 195 (0.4402 230 (0.5077) G G 189 (0.4266 149 (0.3289) MEGA1Gen 630 (0.4626 823 (0.4689) G G 547 (0.4016 647 (0.3687) Gen 630(0.4626 823 (0.4689) G G 547 (0.4016 647 (0.3687) hCV27474984 K3R1(rs375666 MEGA1 add 730 (0.5252 821 (0.4689) G G 367 (0.264 568 (0.3244)LETS add 223 (0.5045 231 (0.5122) G G 109 (0.2466 133 (0.2949) LETS Gen223 (0.5045 231 (0.5122) G G 109 (0.2466 133 (0.2949) Gen 223 (0.5045231 (0.5122) G G 109 (0.2466 133 (0.2949) MEGA1 Gen 730 (0.5252 821(0.4689) G G 367 (0.264 568 (0.3244) Gen 730 (0.5252 821 (0.4689) G G367 (0.264 568 (0.3244) hCV7625318 EKHG4 (rs38681 LETS Gen 79 (0.1787 49(0.1082) G G 361 (0.8167 400 (0.883) MEGA1 Gen 224 (0.1614 236 (0.1346)G G 1151 (0.8293 1501 (0.8562) LETS Gen 79 (0.1787 49 (0.1082) G G 361(0.8167 400 (0.883) Gen 79 (0.1787 49 (0.1082) G G 361 (0.8167 400(0.883) MEGA1 Gen 224 (0.1614 236 (0.1346) G G 1151 (0.8293 1501(0.8562) Gen 224 (0.1614 236 (0.1346) G G 1151 (0.8293 1501 (0.8562)hCV8598986

LR1A (rs48322

LETS rec 176 (0.3982 198 (0.4381) C C 238 (0.5385 209 (0.4624) MEGA1 rec507 (0.3655 696 (0.3984) C C 761 (0.5487 897 (0.5135) LETS Gen 176(0.3982 198 (0.4381) C C 238 (0.5385 209 (0.4624) Gen 176 (0.3982 198(0.4381) C C 238 (0.5385 209 (0.4624) MEGA1 Gen 507 (0.3655 696 (0.3984)C C 761 (0.5487 897 (0.5135) Gen 507 (0.3655 696 (0.3984) C C 761(0.5487 897 (0.5135) hCV926518 P2R5C (rs7467

LETS Gen 94 (0.2127 71 (0.1571) T T 344 (0.7783 376 (0.8319) MEGA1 Gen269 (0.1971 297 (0.1692) T T 1080 (0.7912 1432 (0.816) LETS Gen 94(0.2127 71 (0.1571) T T 344 (0.7783 376 (0.8319) Gen 94 (0.2127 71(0.1571) T T 344 (0.7783 376 (0.8319) MEGA1 Gen 269 (0.1971 297 (0.1692)T T 1080 (0.7912 1432 (0.816) Gen 269 (0.1971 297 (0.1692) T T 1080(0.7912 1432 (0.816) hCV1841975 ROC (rs179981

LETS Gen 215 (0.4864 224 (0.4956) A A 127 (0.2873 147 (0.3252) MEGA1 Gen655 (0.4719 864 (0.4946) A A 410 (0.2954 554 (0.3171) LETS Gen 215(0.4864 224 (0.4956) A A 127 (0.2873 147 (0.3252) Gen 215 (0.4864 224(0.4956) A A 127 (0.2873 147 (0.3252) MEGA1 Gen 655 (0.4719 864 (0.4946)A A 410 (0.2954 554 (0.3171) Gen 655 (0.4719 864 (0.4946) A A 410(0.2954 554 (0.3171) hCV8957432 RAC2 (rs6572) MEGA1 rec 676 (0.4867 862(0.4917) G G 405 (0.2916 557 (0.3177) LETS rec 225 (0.5102 249 (0.5509)G G 117 (0.2653 126 (0.2788) LETS Gen 225 (0.5102 249 (0.5509) G G 117(0.2653 126 (0.2788) Gen 225 (0.5102 249 (0.5509) G G 117 (0.2653 126(0.2788) MEGA1 Gen 676 (0.4867 862 (0.4917) G G 405 (0.2916 557 (0.3177)Gen 676 (0.4867 862 (0.4917) G G 405 (0.2916 557 (0.3177) hCV29271569DH13 (rs162697 LETS add 116 (0.2624 143 (0.3157) T T 317 (0.7172 293(0.6468) MEGA1 add 374 (0.2695 535 (0.305) T T 971 (0.6996 1159 (0.6608)LETS Gen 116 (0.2624 143 (0.3157) T T 317 (0.7172 293 (0.6468) Gen 116(0.2624 143 (0.3157) T T 317 (0.7172 293 (0.6468) MEGA1 Gen 374 (0.2695535 (0.305) T T 971 (0.6996 1159 (0.6608) Gen 374 (0.2695 535 (0.305) TT 971 (0.6996 1159 (0.6608) hCV8703249 DH13 (rs16544 LETS add 117(0.2647 138 (0.3046) G G 315 (0.7127 298 (0.6578) MEGA1 add 376 (0.2711532 (0.303) G G 970 (0.6994 1160 (0.6606) LETS Gen 117 (0.2647 138(0.3046) G G 315 (0.7127 298 (0.6578) Gen 117 (0.2647 38 (0.3046) G G315 (0.7127 298 (0.6578) MEGA1 Gen 376 (0.2711 532 (0.303) G G 970(0.6994 1160 (0.6606) Gen 376 (0.2711 532 (0.303) G G 970 (0.6994 1160(0.6606) hCV8717752 DH13 (rs167121 LETS add 118 (0.267 137 (0.3031) G G317 (0.7172 298 (0.6593) MEGA1 rec 369 (0.2662 518 (0.2955) G G 981(0.7078 1183 (0.6748) LETS Gen 118 (0.267 137 (0.3031) G G 317 (0.7172298 (0.6593) Gen 118 (0.267 137 (0.3031) G G 317 (0.7172 298 (0.6593)MEGA1 Gen 369 (0.2662 518 (0.2955) G G 981 (0.7078 1183 (0.6748) Gen 369(0.2662 518 (0.2955) G G 981 (0.7078 1183 (0.6748) hCV11975296 SELP(rs6131) MEGA1 add 463 (0.3329 504 (0.2882) C C 865 (0.6219 1179(0.6741) LETS add 142 (0.3213 121 (0.2671) C C 273 (0.6176 312 (0.6887)LETS Gen 142 (0.3213 121 (0.2671) C C 273 (0.6176 312 (0.6887) Gen 142(0.3213 121 (0.2671) C C 273 (0.6176 312 (0.6887) MEGA1 Gen 463 (0.3329504 (0.2882) C C 865 (0.6219 1179 (0.6741) Gen 463 (0.3329 504 (0.2882)C C 865 (0.6219 1179 (0.6741) hCV9596963 ERPINA5 (rs611 LETS dom 225(0.5172 224 (0.4989) A A 172 (0.3954 165 (0.3675) MEGA1 dom 632 (0.456775 (0.4434) A A 617 (0.4452 759 (0.4342) LETS Gen 225 (0.5172 224(0.4989) A A 172 (0.3954 165 (0.3675) Gen 225 (0.5172 224 (0.4989) A A172 (0.3954 165 (0.3675) MEGA1 Gen 632 (0.456 775 (0.4434) A A 617(0.4452 759 (0.4342) Gen 632 (0.456 775 (0.4434) A A 617 (0.4452 759(0.4342) hCV16180170 RPINC1 (rs2227

MEGA1 add 259 (0.1863 283 (0.1613) C C 1109 (0.7978 1457 (0.8302) LETSadd 93 (0.2099 70 (0.1549) C C 344 (0.7765 378 (0.8363) LETS Gen 93(0.2099 70 (0.1549) C C 344 (0.7765 378 (0.8363) Gen 93 (0.2099 70(0.1549) C C 344 (0.7765 378 (0.8363) MEGA1 Gen 259 (0.1863 283 (0.1613)C C 1109 (0.7978 1457 (0.8302) Gen 259 (0.1863 283 (0.1613) C C 1109(0.7978 1457 (0.8302) hCV1650632 ERPINC1 (rs587 MEGA1 Gen 615 (0.4593792 (0.4528) T T 533 (0.3981 760 (0.4345) LETS Gen 205 (0.468 174(0.391) T T 184 (0.4201 215 (0.4831) LETS Gen 205 (0.468 174 (0.391) T T184 (0.4201 215 (0.4831) Gen 205 (0.468 174 (0.391) T T 184 (0.4201 215(0.4831) MEGA1 Gen 615 (0.4593 792 (0.4528) T T 533 (0.3981 760 (0.4345)Gen 615 (0.4593 792 (0.4528) T T 533 (0.3981 760 (0.4345) hCV3216426RS2IP (rs73157 LETS dom 218 (0.4955 211 (0.472) A A 135 (0.3068 117(0.2617) MEGA1 dom 707 (0.5061 843 (0.4798) A A 389 (0.2785 473 (0.2692)LETS Gen 218 (0.4955 211 (0.472) A A 135 (0.3068 117 (0.2617) Gen 218(0.4955 211 (0.472) A A 135 (0.3068 117 (0.2617) MEGA1 Gen 707 (0.5061843 (0.4798) A A 389 (0.2785 473 (0.2692) Gen 707 (0.5061 843 (0.4798) AA 389 (0.2785 473 (0.2692) hCV25602230 IRT6 (rs724623 MEGA1 add 46(0.0332 36 (0.0205) T T 1336 (0.9639 1716 (0.9789) LETS add 15 (0.0339 5(0.0111) T T 425 (0.9615 447 (0.9889) LETS Gen 15 (0.0339 5 (0.0111) T T425 (0.9615 447 (0.9889) Gen 15 (0.0339 5 (0.0111) T T 425 (0.9615 447(0.9889) MEGA1 Gen 46 (0.0332 36 (0.0205) T T 1336 (0.9639 1716 (0.9789)Gen 46 (0.0332 36 (0.0205) T T 1336 (0.9639 1716 (0.9789) hCV2086329

ARC (rs495848 MEGA1 rec 631 (0.4556 888 (0.5063) A A 456 (0.3292 570(0.325) LETS rec 205 (0.4628 227 (0.5011) A A 134 (0.3025 150 (0.3311)LETS Gen 205 (0.4628 227 (0.5011) A A 134 (0.3025 150 (0.3311) Gen 205(0.4628 227 (0.5011) A A 134 (0.3025 150 (0.3311) MEGA1 Gen 631 (0.4556888 (0.5063) A A 456 (0.3292 570 (0.325) Gen 631 (0.4556 888 (0.5063) AA 456 (0.3292 570 (0.325) hCV11466393 TACR1 (rs881) LETS add 111 (0.2534139 (0.3138) C C 317 (0.7237 287 (0.6479) MEGA1 add 368 (0.264 508(0.2898) C C 994 (0.7131 1193 (0.6805) LETS Gen 111 (0.2534 139 (0.3138)C C 317 (0.7237 287 (0.6479) Gen 111 (0.2534 139 (0.3138) C C 317(0.7237 287 (0.6479) MEGA1 Gen 368 (0.264 508 (0.2898) C C 994 (0.71311193 (0.6805) Gen 368 (0.264 508 (0.2898) C C 994 (0.7131 1193 (0.6805)hCV3216649 AF1B (rs105456 LETS dom 194 (0.4399 174 (0.3858) G G 197(0.4467 230 (0.51) MEGA1 dom 623 (0.4479 732 (0.4178) G G 608 (0.4371829 (0.4732) LETS Gen 194 (0.4399 174 (0.3858) G G 197 (0.4467 230(0.51) Gen 194 (0.4399 174 (0.3858) G G 197 (0.4467 230 (0.51) MEGA1 Gen623 (0.4479 732 (0.4178) G G 608 (0.4371 829 (0.4732) Gen 623 (0.4479732 (0.4178) G G 608 (0.4371 829 (0.4732) hCV470708 IBS2 (rs109454

LETS add 193 (0.4367 180 (0.3991) G G 199 (0.4502 233 (0.5166) MEGA1 Gen588 (0.4215 747 (0.4264) G G 655 (0.4695 852 (0.4863) LETS Gen 193(0.4367 180 (0.3991) G G 199 (0.4502 233 (0.5166) Gen 193 (0.4367 180(0.3991) G G 199 (0.4502 233 (0.5166) MEGA1 Gen 588 (0.4215 747 (0.4264)G G 655 (0.4695 852 (0.4863) Gen 588 (0.4215 747 (0.4264) G G 655(0.4695 852 (0.4863) hCV3272537 IAM1 (rs497689 LETS dom 214 (0.4853 207(0.458) T T 127 (0.288 155 (0.3429) MEGA1 dom 702 (0.5076 802 (0.4596) TT 404 (0.2921 596 (0.3415) LETS Gen 214 (0.4853 207 (0.458) T T 127(0.288 155 (0.3429) Gen 214 (0.4853 207 (0.458) T T 127 (0.288 155(0.3429) MEGA1 Gen 702 (0.5076 802 (0.4596) T T 404 (0.2921 596 (0.3415)Gen 702 (0.5076 802 (0.4596) T T 404 (0.2921 596 (0.3415) hCV27833944IFSF4 (rs67023

LETS add 89 (0.2014 71 (0.1578) T T 348 (0.7873 376 (0.8356) MEGA1 add256 (0.1847 284 (0.1619) T T 1105 (0.7973 1454 (0.829) LETS Gen 89(0.2014 71 (0.1578) T T 348 (0.7873 376 (0.8356) Gen 89 (0.2014 71(0.1578) T T 348 (0.7873 376 (0.8356) MEGA1 Gen 256 (0.1847 284 (0.1619)T T 1105 (0.7973 1454 (0.829) Gen 256 (0.1847 284 (0.1619) T T 1105(0.7973 1454 (0.829) hCV1723643 MODL1 (rs22013 LETS rec 144 (0.3265 173(0.3836) A A 278 (0.6304 256 (0.5676) MEGA1 rec 431 (0.3114 597 (0.3408)A A 894 (0.646 1060 (0.605) LETS Gen 144 (0.3265 173 (0.3836) A A 278(0.6304 256 (0.5676) Gen 144 (0.3265 173 (0.3836) A A 278 (0.6304 256(0.5676) MEGA1 Gen 431 (0.3114 597 (0.3408) A A 894 (0.646 1060 (0.605)Gen 431 (0.3114 597 (0.3408) A A 894 (0.646 1060 (0.605) hCV7581501 SP45(rs132371 LETS Gen 99 (0.2235 73 (0.1611) G G 335 (0.7562 373 (0.8234)MEGA1 Gen 287 (0.2062 367 (0.209) G G 1079 (0.7751 1372 (0.7813) LETSGen 99 (0.2235 73 (0.1611) G G 335 (0.7562 373 (0.8234) Gen 99 (0.223573 (0.1611) G G 335 (0.7562 373 (0.8234) MEGA1 Gen 287 (0.2062 367(0.209) G G 1079 (0.7751 1372 (0.7813) Gen 287 (0.2062 367 (0.209) G G1079 (0.7751 1372 (0.7813) hCV15949414

YLB (rs223462

MEGA1 rec 89 (0.0653 172 (0.0981) G G 1269 (0.931 1581 (0.9014) LETS rec31 (0.0703 51 (0.1138) G G 409 (0.9274 397 (0.8862) LETS Gen 31 (0.070351 (0.1138) G G 409 (0.9274 397 (0.8862) Gen 31 (0.0703 51 (0.1138) G G409 (0.9274 397 (0.8862) MEGA1 Gen 89 (0.0653 172 (0.0981) G G 1269(0.931 1581 (0.9014) Gen 89 (0.0653 172 (0.0981) G G 1269 (0.931 1581(0.9014) hCV356522 TB41 (rs107322 LETS dom 81 (0.1828 63 (0.1391) C C356 (0.8036 386 (0.8521) MEGA1 dom 274 (0.1975 289 (0.1646) C C 1091(0.7866 1448 (0.8246) LETS Gen 81 (0.1828 63 (0.1391) C C 356 (0.8036386 (0.8521) Gen 81 (0.1828 63 (0.1391) C C 356 (0.8036 386 (0.8521)MEGA1 Gen 274 (0.1975 289 (0.1646) C C 1091 (0.7866 1448 (0.8246) Gen274 (0.1975 289 (0.1646) C C 1091 (0.7866 1448 (0.8246) hCV25596789JF544 (rs651013 LETS add 29 (0.0658 13 (0.0288) C C 410 (0.9297 438(0.9712) MEGA1 add 76 (0.0544 64 (0.0364) C C 1320 (0.9449 1693 (0.9636)LETS Gen 29 (0.0658 13 (0.0288) C C 410 (0.9297 438 (0.9712) Gen 29(0.0658 13 (0.0288) C C 410 (0.9297 438 (0.9712) MEGA1 Gen 76 (0.0544 64(0.0364) C C 1320 (0.9449 1693 (0.9636) Gen 76 (0.0544 64 (0.0364) C C1320 (0.9449 1693 (0.9636) hCV25951992

INT (rs110053

MEGA1 dom 46 (0.033 30 (0.0171) C C 1345 (0.9635 1725 (0.9823) LETS dom22 (0.0499 9 (0.0199) C C 419 (0.9501 442 (0.9779) LETS Gen 22 (0.0499 9(0.0199) C C 419 (0.9501 442 (0.9779) Gen 22 (0.0499 9 (0.0199) C C 419(0.9501 442 (0.9779) MEGA1 Gen 46 (0.033 30 (0.0171) C C 1345 (0.96351725 (0.9823) Gen 46 (0.033 30 (0.0171) C C 1345 (0.9635 1725 (0.9823)

indicates data missing or illegible when filed

TABLE 21 Unadjusted association of 92 SNPs with DVT in LETS (p <= 0.05)that have not been tested in MEGA-1 Non Allele Risk Risk (CONTROL markerannotation P-value parameter Model OR (95% CI) Allele Allele frq GenothCV10008773 ANK1 0.04327 CC_vs_CT + TT rec 1.31 C T T (0.2732 T T(rs750625) (1.00828819022294-1.71) hCV11342584 (rs6696864) 0.03793AT_vs_TT Gen 1.36 (1.02-1.81) A T A (0.3825 A A hCV11503431 FGG 4.6E−05TT_vs_CC Gen 3.01 (1.77-5.11) T C T (0.2622 T T (rs2066861) 9.5E−05TT_vs_TC + CC rec 2.78 T C T (0.2622 T T (1.66280836758397-4.64) 0.00035T_vs_C add 1.46 T C T (0.2622 T T (1.18656074071138-1.8) 0.01879 TT+TC_vs_CC dom 1.37 T C T (0.2622 T T (1.05370601437504-1.78) hCV11559107UNC5C 0.00338 AG_vs_GG Gen 1.54 (1.15-2.06) A G A (0.1837 A A(rs2626053) 0.00999 AA + AG_vs_GG dom 1.44 (1.09-1.89) A G A (0.1837 A AhCV11853483 FGG 5.5E−05 AA_vs_GG Gen 2.98 A G A (0.2605 A A (rs12644950)(1.753373778484-5.07) 0.00014 AA_vs_AG + GG rec 2.72 A G A (0.2605 A A(1.62669691396322-4.55) 0.00028 A_vs_G add 1.47 A G A (0.2605 A A(1.19493352233274-1.81) 0.01296 AA + AG_vs_GG dom 1.4 A G A (0.2605 A A(1.07313147656834-1.82) hCV11853496 FGG 6.8E−05 TT_vs_AA Gen 2.89 T A T(0.2622 T T (rs7654093) (1.71409632424687-4.87) 0.00016 TT_vs_TA + AArec 2.65 T A T (0.2622 T T (1.59864873064354-4.4) 0.00036 T_vs_A add1.46 T A T (0.2622 T T (1.18479576515509-1.79) 0.01572 TT + TA_vs_AA dom1.38 T A T (0.2622 T T (1.06306565580364-1.8) hCV11942562 ACE (rs4343)0.04168 AA + AG_vs_GG dom 1.39 A G G (0.5088 G G (1.01235519054438-1.9)hCV11962159 (rs2000745) 0.03396 TT_vs_CC Gen 9.4 T C T (0.082 T T(1.1848774278982-74.54) 0.03409 TT_vs_TC + CC rec 9.37 T C T (0.082 T T(1.1829594063581-74.3) hCV11975250 F5 (rs6025) 6.6E−12 TT + TC_vs_CC dom7.67 (4.29-13.71) T C T (0.0155 T T 8.6E−12 AA + AG_vs_GG dom 7.17(4.07-12.62) A G T (0.0155 T T 1.6E−11 T_vs_C add 7.19 (4.05-12.77) T CT (0.0155 T T 1.9E−11 A_vs_G add 6.74 (3.86-11.77) A G T (0.0155 T T8.2E−11 TC_vs_CC Gen 6.96 (3.88-12.5) T C T (0.0155 T T 1.1E−10 AG_vs_GGGen 6.51 (3.68-11.5) A G T (0.0155 T T hCV11975651 SERPINC1 0.04802GG_vs_GC + CC rec 0.27 G C G (0.1098 G G (rs677)(0.0759132784778174-0.99) hCV11975658 (rs1951626) 0.03516 AG_vs_GG Gen1.35 (1.02-1.78) A G A (0.3 A A 0.03523 AA + AG_vs_GG dom 1.33(1.02-1.73) A G A (0.3 A A hCV1198623 KRT8 0.00813 GG_vs_CC Gen 1.76(1.16-2.68) G C C (0.3595 C C (rs2638504) 0.01655 G_vs_C add 1.26(1.04-1.52) G C C (0.3595 C C 0.03471 GC_vs_CC Gen 1.58 (1.03-2.42) G CC (0.3595 C C hCV12098639 RIC8A 0.01529 CG_vs_GG Gen 2.72 C G G (0.1887G G (rs3216) (1.21159130646804-6.1) 0.01785 CC + CG_vs_GG dom 2.57 C G G(0.1887 G G (1.17720092620202-5.63) 0.02169 CC_vs_GG Gen 2.51 C G G(0.1887 G G (1.14432781614601-5.52) hCV1376206 NLRP2 0.04509 CT_vs_TTGen 1.33 C T C (0.2777 C C (rs10412915) (1.00618961419825-1.75)hCV1376246 NLRP2 0.04168 AA_vs_AC + CC rec 1.37 A C C (0.5121 C C(rs12768) (1.01192726345419-1.85) hCV1420741 (rs444124) 0.01513 CC_vs_GGGen 1.8 C G C (0.2739 C C (1.11978427423371-2.88) 0.02069 CC_vs_CG + GGrec 1.71 C G C (0.2739 C C (1.0857630416532-2.7) 0.03078 C_vs_G add 1.25C G C (0.2739 C C (1.02065803823507-1.52) hCV1455329 (rs16018) 0.0104GA_vs_AA Gen 1.44 G A G (0.2942 G G (1.08866000283568-1.89) 0.03679 GG +GA_vs_AA dom 1.32 G A G (0.2942 G G (1.01735211455419-1.72) hCV15864094DARS2 0.02341 GG + GA_vs_AA dom 1.54 G A G (0.0668 G G (rs2068871)(1.05976036974367-2.23) 0.02708 G_vs_A add 1.46 G A G (0.0668 G G(1.04392416525319-2.05) 0.03009 GA_vs_AA Gen 1.53 G A G (0.0668 G G(1.04171464630086-2.24) hCV15947925 TNFRSF14 0.0278 TT + TC_vs_CC dom4.17 T C T (0.0033 T T (rs2234163) (1.16858968730866-14.86) 0.02805T_vs_C add 4.02 T C T (0.0033 T T (1.16184582447559-13.94) 0.04069TC_vs_CC Gen 3.82 T C T (0.0033 T T (1.05841588676064-13.79) hCV15953063(rs2953331) 0.01795 AA + AG_vs_GG dom 1.38 A G A (0.3308 A A(1.05693553923995-1.8) 0.02267 AG_vs_GG Gen 1.39 A G A (0.3308 A A(1.0470340893344-1.84) 0.04192 A_vs_G add 1.22 A G A (0.3308 A A(1.00735955225147-1.48) hCV15956054 SERPINC1 0.04188 TC_vs_CC Gen 1.42 TC T (0.1087 T T (rs2227594) (1.01288299286844-1.98) hCV15956055 SERPINC10.04439 TG_vs_GG Gen 1.41 (1.01-1.98) T G T (0.1084 T T (rs2227593)hCV15956059 SERPINC1 0.02277 T_vs_C add 1.44 T C T (0.0865 T T(rs2227592) (1.05163705309124-1.96) 0.02759 TT + TC_vs_CC dom 1.46 T C T(0.0865 T T (1.04229099896258-2.03) 0.04197 TC_vs_CC Gen 1.42 T C T(0.0865 T T (1.01292745754821-2) hCV15977624 RDH13 0.04128 AA_vs_AG + GGrec 1.73 (1.02-2.93) A G A (0.2461 A A (rs2305543) hCV16000557 LOC3909880.00253 TT_vs_CC Gen 1.81 T C T (0.4302 T T (rs2377041)(1.23100609226457-2.65) 0.00283 T_vs_C add 1.34 T C T (0.4302 T T(1.10500557605069-1.62) 0.0076 TT_vs_TC + CC rec 1.56 (1.13-2.16) T C T(0.4302 T T 0.02713 TT + TC_vs_CC dom 1.39 T C T (0.4302 T T(1.03825477779782-1.87) hCV1605386 PKNOX1 0.00313 GA_vs_AA Gen 2.14 G AA (0.311 A A (rs234736) (1.29136514770623-3.54) 0.0126 GG + GA_vs_AA dom1.85 G A A (0.311 A A (1.14079578150342-3) hCV16135173 (rs2146372)0.02501 CC + CG_vs_GG dom 1.47 C G C (0.0878 C C (1.04923410893692-2.05)0.02618 CG_vs_GG Gen 1.48 C G C (0.0878 C C (1.04735910608363-2.08)0.03375 C_vs_G add 1.39 C G C (0.0878 C C (1.02581539781861-1.89)hCV18996 ANKS1B 0.04369 TT_vs_CC Gen 1.99 T C C (0.2434 C C (rs638177)(1.01964405681199-3.88) 0.04845 TT + TC_vs_CC dom 1.94 T C C (0.2434 C C(1.00452097379001-3.76) hCV1900162 PTPN22 0.01558 TC_vs_CC Gen 0.07(0.01-0.61) T C C (0.1221 C C (rs11102685) 0.03279 TT + TC_vs_CC dom 0.1(0.01-0.83) T C C (0.1221 C C 0.04005 TT_vs_CC Gen 0.11 (0.01-0.91) T CC (0.1221 C C hCV1937195 CCDC8 0.01441 G_vs_A add 1.43 G A A (0.1358 A A(rs34186470) (1.07317264786011-1.89) 0.01494 GG_vs_GA + AA rec 1.5 G A A(0.1358 A A (1.0815208090679-2.07) hCV1974936 (rs4648648) 0.01009CC_vs_CT + TT rec 1.48 C T T (0.5088 T T (1.09857002225632-2) 0.0232C_vs_T add 1.25 C T T (0.5088 T T (1.03042165019262-1.5) 0.02746CC_vs_TT Gen 1.53 C T T (0.5088 T T (1.04851513911575-2.24) hCV1974951TNFRSF14 0.01935 GG_vs_GA + AA rec 1.42 G A A (0.4945 A A (rs2234161)(1.05893671316625-1.92) hCV1974967 (rs2147905) 0.01956 AA_vs_AG + GG rec1.43 A G G (0.5066 G G (1.0586829787411-1.92) 0.0449 A_vs_G add 1.21 A GG (0.5066 G G (1.0043557390248-1.46) hCV22272816 GLOD4 0.0413 GG_vs_GA +AA rec 1.32 G A A (0.2969 A A (rs2249542) (1.01088520538692-1.71)0.04909 G_vs_A add 1.23 G A A (0.2969 A A (1.00081269894164-1.5)hCV25611352 RAF1 0.00089 TC_vs_CC Gen 3.3 T C C (0.2113 C C (rs3729926)(1.63135248280203-6.66) 0.00364 TT + TC_vs_CC dom 2.73 T C C (0.2113 C C(1.38738506813726-5.37) 0.00907 TT_vs_CC Gen 2.48 T C C (0.2113 C C(1.25420196929067-4.92) hCV25649928 DEGS1 ( ) 0.00685 G_vs_A add 2.58(1.3-5.12) G A G (0.0135 G G GA_vs_AA Gen 2.58 (1.3-5.12) G A G (0.0135G G GG + GA_vs_AA dom 2.58 (1.3-5.12) G A G (0.0135 G G hCV25767872KIAA1546 0.04821 A_vs_G add 2.1 A G A (0.0121 A A (rs6843141)(1.00587211662689-4.38) AA + AG_vs_GG dom 2.1 A G A (0.0121 A A(1.00587211662689-4.38) AG_vs_GG Gen 2.1 A G A (0.0121 A A(1.00587211662689-4.38) hCV2605707 CDK6 0.04581 CC_vs_GG Gen 1.8 C G G(0.2655 G G (rs42041) (1.01098902434728-3.2) hCV26338456 SDCCAG8 0.04489GG + GA_vs_AA dom 1.38 G A A (0.5 A A (rs10927011)(1.00743666566744-1.9) hCV26338482 SDCCAG8 0.02994 TT_vs_CC Gen 1.74 T CT (0.2711 T T (rs10803143) (1.05555612599845-2.88) 0.04165 TT_vs_TC + CCrec 1.66 T C T (0.2711 T T (1.0193099474508-2.7) hCV26887434 RGS70.04698 CC_vs_AA Gen 1.47 C A C (0.4248 C C (rs12723522)(1.0051583138784-2.15) hCV26895255 GP6 0.04243 CC_vs_CT + TT rec 2.03 CT C (0.2174 C C (rs11669150) (1.0244638955455-4.02) hCV27020269(rs7659613) 0.02343 CC_vs_GG Gen 1.56 C G C (0.4047 C C(1.06156384252267-2.28) 0.02703 C_vs_G add 1.24 C G C (0.4047 C C(1.02429403887418-1.49) 0.04138 CC_vs_CG + GG rec 1.42 C G C (0.4047 C C(1.01385341422313-1.99) hCV27102953 LOC647718 0.00713 TT_vs_CC Gen 1.7 TC T (0.4519 T T (rs4648360) (1.15505198766522-2.5) 0.00775 T_vs_C add1.3 T C T (0.4519 T T (1.07164121464812-1.58) 0.01291 TT_vs_TC + CC rec1.5 T C T (0.4519 T T (1.08992095886976-2.07) hCV27102978 LOC6477180.00037 C_vs_A add 1.43 C A A (0.5344 A A (rs7537581)(1.17286039578863-1.73) 0.00039 CC_vs_AA Gen 2.03 C A A (0.5344 A A(1.37196942703233-2.99) 0.00101 CC_vs_CA + AA rec 1.69 C A A (0.5344 A A(1.23512192592463-2.3) 0.01374 CC + CA_vs_AA dom 1.49 C A A (0.5344 A A(1.08473599302907-2.04) hCV27103080 (rs4648459) 0.00385 TT_vs_GG Gen1.76 T G T (0.4305 T T (1.19923635734498-2.58) 0.00458 T_vs_G add 1.32 TG T (0.4305 T T (1.08862166155631-1.59) 0.00807 TT_vs_TG + GG rec 1.55 TG T (0.4305 T T (1.12162097064999-2.15) 0.04586 TT + TG_vs_GG dom 1.35 TG T (0.4305 T T (1.00549674456945-1.81) hCV27103182 (rs4609377) 0.00077C_vs_T add 1.39 C T T (0.5133 T T (1.14837160766132-1.69) 0.00082CC_vs_TT Gen 1.94 C T T (0.5133 T T (1.31528974268535-2.86) 0.00467CC_vs_CT + TT rec 1.54 C T T (0.5133 T T (1.14249698884992-2.08) 0.00898CC + CT_vs_TT dom 1.54 C T T (0.5133 T T (1.11419540235736-2.13)hCV27103188 (rs7511879) 0.00386 GG_vs_GA + AA rec 1.59 G A G (0.4636 G G(1.16090265496612-2.18) 0.00463 GG_vs_AA Gen 1.75 G A G (0.4636 G G(1.18753475086407-2.57) 0.00485 G_vs_A add 1.32 G A G (0.4636 G G(1.08809986054585-1.6) hCV27103189 (rs12031493) 0.00933 G_vs_A add 1.29G A A (0.5133 A A (1.06498516575119-1.57) 0.0103 GG_vs_AA Gen 1.66 G A A(0.5133 A A (1.12671323564467-2.44) 0.01303 GG_vs_GA + AA rec 1.47 G A A(0.5133 A A (1.08458487392409-1.99) hCV27103207 (rs6424062) 0.00385AA_vs_GG Gen 1.76 A G A (0.4305 A A (1.19923635734499-2.58) 0.00453A_vs_G add 1.32 A G A (0.4305 A A (1.08899212231946-1.59) 0.0085AA_vs_AG + GG rec 1.55 A G A (0.4305 A A (1.11833165727631-2.15) 0.04367AA + AG_vs_GG dom 1.35 A G A (0.4305 A A (1.00859469798602-1.81)hCV2716314 CTSB (rs8005) 0.04236 A_vs_C add 1.24 A C A (0.2522 A A(1.00756185015975-1.54) hCV2734332 39783 0.00283 GA_vs_AA Gen 2.07(1.28-3.33) G A A (0.323 A A (rs10759757) 0.01256 GG_vs_AA Gen 1.82(1.14-2.91) G A A (0.323 A A hCV27476043 RDH13 0.03332 AA_vs_AG + GG rec2.8 A G A (0.1512 A A (rs3745912) (1.08474967907152-7.22) 0.04 AA_vs_GGGen 2.71 A G A (0.1512 A A (1.04653998737852-7.01) hCV27937396(rs4634201) 0.04871 CC_vs_TT Gen 1.97 C T C (0.1858 C C(1.00383697586705-3.87) hCV2811695 FTO 0.00707 C_vs_A add 1.46(1.11-1.93) C A C (0.1056 C C (rs940214) 0.01189 CC + CA_vs_AA dom 1.49(1.09-2.04) C A C (0.1056 C C 0.03143 CA_vs_AA Gen 1.43 (1.03-1.97) C AC (0.1056 C C hCV2852784 CYP17A1 0.01777 A_vs_G add 1.27 (1.04-1.54) A GG (0.412 G G (rs743572) 0.0271 AA_vs_GG Gen 1.59 (1.05-2.41) A G G(0.412 G G 0.03431 AA_vs_AG + GG rec 1.34 (1.02-1.77) A G G (0.412 G GhCV2892855 FGG 0.00076 CC_vs_CT + TT rec 1.62 C T T (0.4546 T T(rs6536024) (1.22305766829666-2.14) 0.0009 C_vs_T add 1.39 C T T (0.4546T T (1.14291480827487-1.68) 0.00284 CC_vs_TT Gen 1.83 C T T (0.4546 T T(1.22982199650641-2.71) hCV2892869 (rs13109457) 0.00029 AA_vs_GG Gen 2.5A G A (0.2772 A A (1.52334238718455-4.1) 0.00037 AA_vs_AG + GG rec 2.38A G A (0.2772 A A (1.47584712337765-3.83) 0.00249 A_vs_G add 1.37 A G A(0.2772 A A (1.11676316556903-1.68) hCV2892893 (rs12648258) 0.01399A_vs_T add 1.32 A T A (0.1947 A A (1.05814542701223-1.65) 0.01963AA_vs_TT Gen 2.08 A T A (0.1947 A A (1.12423038179963-3.84) 0.033AA_vs_AT + TT rec 1.93 A T A (0.1947 A A (1.05470532431105-3.55) 0.04454AA + AT_vs_TT dom 1.32 A T A (0.1947 A A (1.00678919794171-1.73)hCV2892905 PLRG1 0.03327 C_vs_T add 1.27 C T C (0.2103 C C (rs12642770)(1.01895685789595-1.58) 0.04994 CC_vs_TT Gen 1.77 C T C (0.2103 C C(1.00015868058748-3.15) hCV2892918 (rs12511469) 0.02229 A_vs_T add 1.3 AT A (0.1973 A A (1.03749332929128-1.62) 0.03037 AA_vs_TT Gen 1.95 A T A(0.1973 A A (1.06535995989442-3.57) 0.04836 AA_vs_AT + TT rec 1.82 A T A(0.1973 A A (1.00432829446122-3.31) hCV2892926 (rs7662567) 0.00586C_vs_T add 1.36 C T C (0.1984 C C (1.09357836651693-1.7) 0.00915CC_vs_TT Gen 2.21 C T C (0.1984 C C (1.21714661169315-4.01) 0.01776CC_vs_CT + TT rec 2.03 C T C (0.1984 C C (1.13094724249255-3.66) 0.02387CC + CT_vs_TT dom 1.37 C T C (0.1984 C C (1.04211330687034-1.79)hCV2892927 (rs13123551) 0.01436 AA_vs_AT + TT rec 1.42 A T T (0.4524 T T(1.07291037992945-1.89) 0.02592 A_vs_T add 1.24 A T T (0.4524 T T(1.02650891219607-1.51) hCV29521317 LIMD1 0.02272 G_vs_A add 1.62(1.07-2.45) G A G (0.0454 G G (rs7648441) 0.02712 GG + GA_vs_AA dom 1.6(1.05-2.44) G A G (0.0454 G G 0.03349 GA_vs_AA Gen 1.58 (1.04-2.4) G A G(0.0454 G G hCV29983641 (rs10008078) 0.00588 AA_vs_GG Gen 2.34 A G A(0.1993 A A (1.27718823993844-4.27) 0.00921 A_vs_G add 1.34 (1.08-1.67)A G A (0.1993 A A 0.00957 AA_vs_AG + GG rec 2.2 (1.21-3.98) A G A(0.1993 A A hCV30002208 (rs9402927) 0.04695 AA + AG_vs_GG dom 1.46(1.01-2.12) A G G (0.4069 G G hCV30040828 TNFSF4 0.03454 TT + TC_vs_CCdom 1.45 (1.03-2.04) T C T (0.0824 T T (rs6700269) 0.03713 TC_vs_CC Gen1.45 T C T (0.0824 T T (1.02251331249644-2.06) 0.04223 T_vs_C add 1.39(1.01-1.91) T C T (0.0824 T T hCV30548253 (rs9425773) 0.02996 AC_vs_CCGen 2.77 A C C (0.1478 C C (1.10401013563533-6.96) hCV305844 LOC7280770.0275 CC_vs_CG + GG rec 1.49 (1.05-2.13) C G C (0.383 C C (rs4823562)hCV30711231 (rs12642469) 0.02106 A_vs_G add 1.3 (1.04-1.62) A G A (0.198A A 0.02334 AA_vs_GG Gen 2.01 A G A (0.198 A A (1.09904034857764-3.66)0.03665 AA_vs_AG + GG rec 1.88 A G A (0.198 A A (1.04000430618758-3.41)hCV31475431 MMEL1 0.0372 GG_vs_GT + TT rec 1.42 G T T (0.117 T T(rs12133956) (1.02106867570514-1.98) hCV31863982 (rs7659024) 2.2E−05AA_vs_GG Gen 3.13 A G A (0.2622 A A (1.84942397608161-5.31) 4.6E−05AA_vs_AG + GG rec 2.89 A G A (0.2622 A A (1.73628966491938-4.82) 0.0002A_vs_G add 1.48 (1.2-1.82) A G A (0.2622 A A 0.01564 AA + AG_vs_GG dom1.38 (1.06-1.8) A G A (0.2622 A A hCV31965333 (rs10797390) 0.00973CC_vs_TT Gen 1.67 C T T (0.4934 T T (1.13170137567537-2.46) 0.01032C_vs_T add 1.29 (1.06-1.56) C T T (0.4934 T T 0.02629 CC + CT_vs_TT dom1.45 (1.05-2.02) C T T (0.4934 T T hCV31997958 CHMP7 0.00266 GG_vs_GA +AA rec 1.79 G A G (0.3516 G G (rs12544038) (1.22451031007049-2.62)0.00301 GG_vs_AA Gen 1.86 G A G (0.3516 G G (1.23542884303164-2.81)0.00969 G_vs_A add 1.29 (1.06-1.56) G A G (0.3516 G G hCV3205858 PXDNL0.04375 CC_vs_CT + TT rec 1.47 C T C (0.3565 C C (rs2979122)(1.01081147987946-2.13) hCV3210786 C1orf164 0.00202 CC_vs_CT + TT rec2.02 C T C (0.2962 C C (rs11582970) (1.29239242014763-3.15) 0.00463CC_vs_TT Gen 1.96 C T C (0.2962 C C (1.22969863581067-3.12) hCV32212664(rs12642646) 0.00716 AA_vs_AG + GG rec 1.5 A G G (0.4878 G G(1.11615682413902-2.01) hCV7429782 FGG 0.01428 T_vs_A add 1.3 (1.05-1.6)T A A (0.3131 A A (rs1118823) 0.0193 TT_vs_TA + AA rec 1.37 T A A(0.3131 A A (1.05227516552433-1.78) hCV7429793 (rs1025154) 0.01309C_vs_T add 1.32 (1.06-1.65) C T C (0.198 C C 0.02761 CC_vs_TT Gen 1.97 CT C (0.198 C C (1.07778558946615-3.61) 0.03429 CC + CT_vs_TT dom 1.34(1.02-1.75) C T C (0.198 C C 0.04931 CC_vs_CT + TT rec 1.82 C T C (0.198C C (1.00180479357554-3.3) hCV788647 (rs729045) 0.01217 AA_vs_GG Gen1.69 (1.12-2.54) A G G (0.4393 G G 0.01497 A_vs_G add 1.28 (1.05-1.55) AG G (0.4393 G G hCV813581 OR4C11 0.01556 T_vs_G add 1.47 (1.08-2) T G T(0.0583 T T (rs491160) 0.02979 TT + TG_vs_GG dom 1.61 (1.05-2.47) T G T(0.0583 T T 0.03083 TT_vs_GG Gen 2.33 (1.08-5.01) T G T (0.0583 T T0.03607 TT_vs_TG + GG rec 2.27 (1.05-4.88) T G T (0.0583 T T hCV8727391C17orf81 0.01705 AG_vs_GG Gen 1.71 (1.1-2.66) A G G (0.3595 G G(rs414206) hCV8857351 RGS7 0.03561 TT_vs_TC + CC rec 1.42 (1.02-1.98) TC T (0.4248 T T (rs2341021) hCV8911768 SERPINC1 0.01702 T_vs_C add 1.46(1.07-1.98) T C T (0.0856 T T (rs941988) 0.02739 TC_vs_CC Gen 1.47(1.04-2.08) T C T (0.0856 T T hCV8919450 F5 (rs6017) 0.00317 AA_vs_AG +GG rec 1.5 (1.15-1.97) A G G (0.2567 G G 0.00978 A_vs_G add 1.33(1.07-1.65) A G G (0.2567 G G hCV8941510 CDSN 0.04988 CC_vs_AA Gen 2.46(1-6.07) C A C (0.1411 C C (rs1042127) hCV9114656 CFHR5 0.04258 C_vs_Tadd 1.42 (1.01-1.99) C T C (0.0706 C C (rs9427662) hCV9680592 MIPEP0.03902 GA_vs_AA Gen 0.55 (0.31-0.97) G A A (0.2539 A A (rs17079372)hDV70683187 (rs16846561) 0.02204 G_vs_C add 1.43 (1.05-1.93) G C G (0.09G G 0.03622 GC_vs_CC Gen 1.44 (1.02-2.02) G C G (0.09 G G hDV70683212RC3H1 0.04442 G_vs_C add 1.45 (1.01-2.07) G C G (0.0633 G G (rs16846593)hDV70683382 RABGAP1L 0.04002 C_vs_G add 1.49 (1.02-2.18) C G C (0.0515 CC (rs16846815) hDV70965621 (rs17534243) 0.0283 GA_vs_AA Gen 1.37(1.03-1.81) G A G (0.2157 G G CONTROL CONTROL CONTROL cnt CASE cnt cntcnt CASE cnt (CONTROL (CASE (CONTROL CASE cnt (CONTROL marker annotationP-value (CASE frq frq) Genot2 frq2 frq)2 Genot3 (CASE frq3 frq)3hCV10008773 ANK1 0.04327 32 (0.0722) 33 (0.073) T C 148 (0.3341 181(0.4004) C C 263 (0.5937 238 (0.5265) (rs750625) hCV11342584 (rs6696864)0.03793 66 (0.15) 73 (0.1619) A T 225 (0.5114 199 (0.4412) T T 149(0.3386 179 (0.3969) hCV11503431 FGG 4.6E−05 55 (0.1244) 22 (0.0487) T C190 (0.4299 193 (0.427) C C 197 (0.4457 237 (0.5243) (rs2066861) 9.5E−0555 (0.1244) 22 (0.0487) T C 190 (0.4299 193 (0.427) C C 197 (0.4457 237(0.5243) 0.00035 55 (0.1244) 22 (0.0487) T C 190 (0.4299 193 (0.427) C C197 (0.4457 237 (0.5243) 0.01879 55 (0.1244) 22 (0.0487) T C 190 (0.4299193 (0.427) C C 197 (0.4457 237 (0.5243) hCV11559107 UNC5C 0.00338 19(0.0431) 24 (0.0535) A G 156 (0.3537 117 (0.2606) G G 266 (0.6032 308(0.686) (rs2626053) 0.00999 19 (0.0431) 24 (0.0535) A G 156 (0.3537 117(0.2606) G G 266 (0.6032 308 (0.686) hCV11853483 FGG 5.5E−05 54 (0.1224)22 (0.0488) A G 191 (0.4331 191 (0.4235) G G 196 (0.4444 238 (0.5277)(rs12644950) 0.00014 54 (0.1224) 22 (0.0488) A G 191 (0.4331 191(0.4235) G G 196 (0.4444 238 (0.5277) 0.00028 54 (0.1224) 22 (0.0488) AG 191 (0.4331 191 (0.4235) G G 196 (0.4444 238 (0.5277) 0.01296 54(0.1224) 22 (0.0488) A G 191 (0.4331 191 (0.4235) G G 196 (0.4444 238(0.5277) hCV11853496 FGG 6.8E−05 55 (0.1244) 23 (0.0509) T A 190 (0.4299191 (0.4226) A A 197 (0.4457 238 (0.5265) (rs7654093) 0.00016 55(0.1244) 23 (0.0509) T A 190 (0.4299 191 (0.4226) A A 197 (0.4457 238(0.5265) 0.00036 55 (0.1244) 23 (0.0509) T A 190 (0.4299 191 (0.4226) AA 197 (0.4457 238 (0.5265) 0.01572 55 (0.1244) 23 (0.0509) T A 190(0.4299 191 (0.4226) A A 197 (0.4457 238 (0.5265) hCV11942562 ACE(rs4343) 0.04168 89 (0.2014) 117 (0.2588) G A 232 (0.5249 226 (0.5) A A121 (0.2738 109 (0.2412) hCV11962159 (rs2000745) 0.03396 9 (0.0204) 1(0.0022) T C 70 (0.1587 72 (0.1596) C C 362 (0.8209 378 (0.8381) 0.034099 (0.0204) 1 (0.0022) T C 70 (0.1587 72 (0.1596) C C 362 (0.8209 378(0.8381) hCV11975250 F5 (rs6025) 6.6E−12 8 (0.0181) 0 (0) T C 79 (0.178714 (0.031) C C 355 (0.8032 438 (0.969) 8.6E−12 8 (0.0181) 0 (0) T C 79(0.1787 14 (0.031) C C 355 (0.8032 438 (0.969) 1.6E−11 8 (0.0181) 0 (0)T C 79 (0.1787 14 (0.031) C C 355 (0.8032 438 (0.969) 1.9E−11 8 (0.0181)0 (0) T C 79 (0.1787 14 (0.031) C C 355 (0.8032 438 (0.969) 8.2E−11 8(0.0181) 0 (0) T C 79 (0.1787 14 (0.031) C C 355 (0.8032 438 (0.969)1.1E−10 8 (0.0181) 0 (0) T C 79 (0.1787 14 (0.031) C C 355 (0.8032 438(0.969) hCV11975651 SERPINC1 0.04802 3 (0.0068) 11 (0.0244) G C 96(0.2177 77 (0.1707) C C 342 (0.7755 363 (0.8049) (rs677) hCV11975658(rs1951626) 0.03516 43 (0.0973) 41 (0.0911) A G 213 (0.4819 188 (0.4178)G G 186 (0.4208 221 (0.4911) 0.03523 43 (0.0973) 41 (0.0911) A G 213(0.4819 188 (0.4178) G G 186 (0.4208 221 (0.4911) hCV1198623 KRT80.00813 45 (0.1016) 72 (0.1593) C G 179 (0.4041 181 (0.4004) G G 219(0.4944 199 (0.4403) (rs2638504) 0.01655 45 (0.1016) 72 (0.1593) C G 179(0.4041 181 (0.4004) G G 219 (0.4944 199 (0.4403) 0.03471 45 (0.1016) 72(0.1593) C G 179 (0.4041 181 (0.4004) G G 219 (0.4944 199 (0.4403)hCV12098639 RIC8A 0.01529 9 (0.0204) 23 (0.0508) G C 133 (0.3009 125(0.2759) C C 300 (0.6787 305 (0.6733) (rs3216) 0.01785 9 (0.0204) 23(0.0508) G C 133 (0.3009 125 (0.2759) C C 300 (0.6787 305 (0.6733)0.02169 9 (0.0204) 23 (0.0508) G C 133 (0.3009 125 (0.2759) C C 300(0.6787 305 (0.6733) hCV1376206 NLRP2 0.04509 38 (0.086) 38 (0.0841) C T199 (0.4502 175 (0.3872) T T 205 (0.4638 239 (0.5288) (rs10412915)hCV1376246 NLRP2 0.04168 107 (0.2415) 112 (0.2472) C A 211 (0.4763 240(0.5298) A A 125 (0.2822 101 (0.223) (rs12768) hCV1420741 (rs444124)0.01513 53 (0.1196) 33 (0.0735) C G 179 (0.4041 180 (0.4009) G G 211(0.4763 236 (0.5256) 0.02069 53 (0.1196) 33 (0.0735) C G 179 (0.4041 180(0.4009) G G 211 (0.4763 236 (0.5256) 0.03078 53 (0.1196) 33 (0.0735) CG 179 (0.4041 180 (0.4009) G G 211 (0.4763 236 (0.5256) hCV1455329(rs16018) 0.0104 35 (0.0792) 46 (0.1018) G A 211 (0.4774 174 (0.385) A A196 (0.4434 232 (0.5133) 0.03679 35 (0.0792) 46 (0.1018) G A 211 (0.4774174 (0.385) A A 196 (0.4434 232 (0.5133) hCV15864094 DARS2 0.02341 6(0.0136) 4 (0.0089) G A 73 (0.1659 52 (0.1158) A A 361 (0.8205 393(0.8753) (rs2068871) 0.02708 6 (0.0136) 4 (0.0089) G A 73 (0.1659 52(0.1158) A A 361 (0.8205 393 (0.8753) 0.03009 6 (0.0136) 4 (0.0089) G A73 (0.1659 52 (0.1158) A A 361 (0.8205 393 (0.8753) hCV15947925 TNFRSF140.0278 1 (0.0023) 0 (0) T C 11 (0.0248 3 (0.0066) C C 431 (0.9729 449(0.9934) (rs2234163) 0.02805 1 (0.0023) 0 (0) T C 11 (0.0248 3 (0.0066)C C 431 (0.9729 449 (0.9934) 0.04069 1 (0.0023) 0 (0) T C 11 (0.0248 3(0.0066) C C 431 (0.9729 449 (0.9934) hCV15953063 (rs2953331) 0.01795 60(0.1364) 55 (0.1217) A G 212 (0.4818 189 (0.4181) G G 168 (0.3818 208(0.4602) 0.02267 60 (0.1364) 55 (0.1217) A G 212 (0.4818 189 (0.4181) GG 168 (0.3818 208 (0.4602) 0.04192 60 (0.1364) 55 (0.1217) A G 212(0.4818 189 (0.4181) G G 168 (0.3818 208 (0.4602) hCV15956054 SERPINC10.04188 4 (0.0092) 11 (0.0247) T C 98 (0.2258 75 (0.1682) C C 332 (0.765360 (0.8072) (rs2227594) hCV15956055 SERPINC1 0.04439 4 (0.0092) 11(0.0248) T G 97 (0.224 74 (0.167) G G 332 (0.7667 358 (0.8081)(rs2227593) hCV15956059 SERPINC1 0.02277 6 (0.0136) 3 (0.0067) T C 93(0.2114 72 (0.1596) C C 341 (0.775 376 (0.8337) (rs2227592) 0.02759 6(0.0136) 3 (0.0067) T C 93 (0.2114 72 (0.1596) C C 341 (0.775 376(0.8337) 0.04197 6 (0.0136) 3 (0.0067) T C 93 (0.2114 72 (0.1596) C C341 (0.775 376 (0.8337) hCV15977624 RDH13 0.04128 39 (0.0882) 24 (0.053)A G 147 (0.3326 175 (0.3863) G G 256 (0.5792 254 (0.5607) (rs2305543)hCV16000557 LOC390988 0.00253 108 (0.246) 78 (0.1729) T C 223 (0.508 232(0.5144) C C 108 (0.246 141 (0.3126) (rs2377041) 0.00283 108 (0.246) 78(0.1729) T C 223 (0.508 232 (0.5144) C C 108 (0.246 141 (0.3126) 0.0076108 (0.246) 78 (0.1729) T C 223 (0.508 232 (0.5144) C C 108 (0.246 141(0.3126) 0.02713 108 (0.246) 78 (0.1729) T C 223 (0.508 232 (0.5144) C C108 (0.246 141 (0.3126) hCV1605386 PKNOX1 0.00313 28 (0.0638) 50(0.1119) A G 213 (0.4852 178 (0.3982) G G 198 (0.451 219 (0.4899)(rs234736) 0.0126 28 (0.0638) 50 (0.1119) A G 213 (0.4852 178 (0.3982) GG 198 (0.451 219 (0.4899) hCV16135173 (rs2146372) 0.02501 6 (0.0136) 5(0.0111) C G 93 (0.2104 69 (0.1533) G G 343 (0.776 376 (0.8356) 0.026186 (0.0136) 5 (0.0111) C G 93 (0.2104 69 (0.1533) G G 343 (0.776 376(0.8356) 0.03375 6 (0.0136) 5 (0.0111) C G 93 (0.2104 69 (0.1533) G G343 (0.776 376 (0.8356) hCV18996 ANKS1B 0.04369 14 (0.0317) 27 (0.0597)C T 161 (0.3643 166 (0.3673) T T 267 (0.6041 259 (0.573) (rs638177)0.04845 14 (0.0317) 27 (0.0597) C T 161 (0.3643 166 (0.3673) T T 267(0.6041 259 (0.573) hCV1900162 PTPN22 0.01558 8 (0.0278) 1 (0.0029) C T48 (0.1667 81 (0.2382) T T 232 (0.8056 258 (0.7588) (rs11102685) 0.032798 (0.0278) 1 (0.0029) C T 48 (0.1667 81 (0.2382) T T 232 (0.8056 258(0.7588) 0.04005 8 (0.0278) 1 (0.0029) C T 48 (0.1667 81 (0.2382) T T232 (0.8056 258 (0.7588) hCV1937195 CCDC8 0.01441 7 (0.0158) 12 (0.0265)A G 72 (0.1625 99 (0.2185) G G 364 (0.8217 342 (0.755) (rs34186470)0.01494 7 (0.0158) 12 (0.0265) A G 72 (0.1625 99 (0.2185) G G 364(0.8217 342 (0.755) hCV1974936 (rs4648648) 0.01009 93 (0.2104) 109(0.2406) T C 217 (0.491 243 (0.5364) C C 132 (0.2986 101 (0.223) 0.023293 (0.2104) 109 (0.2406) T C 217 (0.491 243 (0.5364) C C 132 (0.2986 101(0.223) 0.02746 93 (0.2104) 109 (0.2406) T C 217 (0.491 243 (0.5364) C C132 (0.2986 101 (0.223) hCV1974951 TNFRSF14 0.01935 93 (0.2099) 102(0.2262) A G 214 (0.4831 242 (0.5366) G G 136 (0.307 107 (0.2373)(rs2234161) hCV1974967 (rs2147905) 0.01956 97 (0.2195) 111 (0.245) G A212 (0.4796 237 (0.5232) A A 133 (0.3009 105 (0.2318) 0.0449 97 (0.2195)111 (0.245) G A 212 (0.4796 237 (0.5232) A A 133 (0.3009 105 (0.2318)hCV22272816 GLOD4 0.0413 35 (0.0794) 44 (0.0971) A G 154 (0.3492 181(0.3996) G G 252 (0.5714 228 (0.5033) (rs2249542) 0.04909 35 (0.0794) 44(0.0971) A G 154 (0.3492 181 (0.3996) G G 252 (0.5714 228 (0.5033)hCV25611352 RAF1 0.00089 12 (0.0271) 32 (0.0708) C T 157 (0.3552 127(0.281) T T 273 (0.6176 293 (0.6482) (rs3729926) 0.00364 12 (0.0271) 32(0.0708) C T 157 (0.3552 127 (0.281) T T 273 (0.6176 293 (0.6482)0.00907 12 (0.0271) 32 (0.0708) C T 157 (0.3552 127 (0.281) T T 273(0.6176 293 (0.6482) hCV25649928 DEGS1 ( ) 0.00685 0 (0) 0 (0) G A 29(0.0667 12 (0.027) A A 406 (0.9333 433 (0.973) 0 (0) 0 (0) G A 29(0.0667 12 (0.027) A A 406 (0.9333 433 (0.973) 0 (0) 0 (0) G A 29(0.0667 12 (0.027) A A 406 (0.9333 433 (0.973) hCV25767872 KIAA15460.04821 0 (0) 0 (0) A G 22 (0.0497 11 (0.0243) G G 421 (0.9503 442(0.9757) (rs6843141) 0 (0) 0 (0) A G 22 (0.0497 11 (0.0243) G G 421(0.9503 442 (0.9757) 0 (0) 0 (0) A G 22 (0.0497 11 (0.0243) G G 421(0.9503 442 (0.9757) hCV2605707 CDK6 0.04581 20 (0.0456) 35 (0.0774) G C165 (0.3759 170 (0.3761) C C 254 (0.5786 247 (0.5465) (rs42041)hCV26338456 SDCCAG8 0.04489 86 (0.1946) 113 (0.2506) A G 238 (0.5385 225(0.4989) G G 118 (0.267 113 (0.2506) (rs10927011) hCV26338482 SDCCAG80.02994 45 (0.1025) 29 (0.0644) T C 185 (0.4214 186 (0.4133) C C 209(0.4761 235 (0.5222) (rs10803143) 0.04165 45 (0.1025) 29 (0.0644) T C185 (0.4214 186 (0.4133) C C 209 (0.4761 235 (0.5222) hCV26887434 RGS70.04698 99 (0.224) 78 (0.1726) C A 217 (0.491 228 (0.5044) A A 126(0.2851 146 (0.323) (rs12723522) hCV26895255 GP6 0.04243 25 (0.0566) 13(0.0287) C T 148 (0.3348 171 (0.3775) T T 269 (0.6086 269 (0.5938)(rs11669150) hCV27020269 (rs7659613) 0.02343 95 (0.2154) 73 (0.1619) C G213 (0.483 219 (0.4856) G G 133 (0.3016 159 (0.3525) 0.02703 95 (0.2154)73 (0.1619) C G 213 (0.483 219 (0.4856) G G 133 (0.3016 159 (0.3525)0.04138 95 (0.2154) 73 (0.1619) C G 213 (0.483 219 (0.4856) G G 133(0.3016 159 (0.3525) hCV27102953 LOC647718 0.00713 112 (0.2551) 83(0.1857) T C 227 (0.5171 238 (0.5324) C C 100 (0.2278 126 (0.2819)(rs4648360) 0.00775 112 (0.2551) 83 (0.1857) T C 227 (0.5171 238(0.5324) C C 100 (0.2278 126 (0.2819) 0.01291 112 (0.2551) 83 (0.1857) TC 227 (0.5171 238 (0.5324) C C 100 (0.2278 126 (0.2819) hCV27102978LOC647718 0.00037 85 (0.1923) 118 (0.2616) A C 230 (0.5204 246 (0.5455)C C 127 (0.2873 87 (0.1929) (rs7537581) 0.00039 85 (0.1923) 118 (0.2616)A C 230 (0.5204 246 (0.5455) C C 127 (0.2873 87 (0.1929) 0.00101 85(0.1923) 118 (0.2616) A C 230 (0.5204 246 (0.5455) C C 127 (0.2873 87(0.1929) 0.01374 85 (0.1923) 118 (0.2616) A C 230 (0.5204 246 (0.5455) CC 127 (0.2873 87 (0.1929) hCV27103080 (rs4648459) 0.00385 108 (0.2443)78 (0.1722) T G 223 (0.5045 234 (0.5166) G G 111 (0.2511 141 (0.3113)0.00458 108 (0.2443) 78 (0.1722) T G 223 (0.5045 234 (0.5166) G G 111(0.2511 141 (0.3113) 0.00807 108 (0.2443) 78(0.1722) T G 223 (0.5045 234(0.5166) G G 111 (0.2511 141 (0.3113) 0.04586 108 (0.2443) 78(0.1722) TG 223 (0.5045 234 (0.5166) G G 111 (0.2511 141 (0.3113) hCV27103182(rs4609377) 0.00077 78(0.1761) 112 (0.2478) T C 230 (0.5192 240 (0.531)C C 135 (0.3047 100 (0.2212) 0.00082 78 (0.1761) 112 (0.2478) T C 230(0.5192 240 (0.531) C C 135 (0.3047 100 (0.2212) 0.00467 78 (0.1761)112(0.2478) T C 230 (0.5192 240 (0.531) C C 135 (0.3047 100 (0.2212)0.00898 78 (0.1761) 112 (0.2478) T C 230 (0.5192 240 (0.531) C C 135(0.3047 100 (0.2212) hCV27103188 (rs7511879) 0.00386 120 (0.2715) 86(0.1898) G A 227 (0.5136 248 (0.5475) A A 95 (0.2149 119 (0.2627)0.00463 120 (0.2715) 86 (0.1898) G A 227 (0.5136 248 (0.5475) A A 95(0.2149 119 (0.2627) 0.00485 120 (0.2715) 86 (0.1898) G A 227 (0.5136248 (0.5475) A A 95 (0.2149 119 (0.2627) hCV27103189 (rs12031493)0.00933 86 (0.1959) 110 (0.2434) A G 226 (0.5148 244 (0.5398) G G 127(0.2893 98 (0.2168) 0.0103 86 (0.1959) 110 (0.2434) A G 226 (0.5148 244(0.5398) G G 127 (0.2893 98 (0.2168) 0.01303 86 (0.1959) 110 (0.2434) AG 226 (0.5148 244 (0.5398) G G 127 (0.2893 98 (0.2168) hCV27103207(rs6424062) 0.00385 108 (0.2438) 78 (0.1722) A G 224 (0.5056 234(0.5166) G G 111 (0.2506 141 (0.3113) 0.00453 108 (0.2438) 78 (0.1722) AG 224 (0.5056 234 (0.5166) G G 111 (0.2506 141 (0.3113) 0.0085 108(0.2438) 78 (0.1722) A G 224 (0.5056 234 (0.5166) G G 111 (0.2506 141(0.3113) 0.04367 108 (0.2438) 78 (0.1722) A G 224 (0.5056 234 (0.5166) GG 111 (0.2506 141 (0.3113) hCV2716314 CTSB (rs8005) 0.04236 36 (0.0816)28 (0.0619) A C 188 (0.4263 172 (0.3805) C C 217 (0.4921 252 (0.5575)hCV2734332 39783 0.00283 32 (0.0722) 59 (0.1305) A G 195 (0.4402 174(0.385) G G 216 (0.4876 219 (0.4845) (rs10759757) 0.01256 32 (0.0722) 59(0.135) A G 195 (0.4402 174 (0.385) G G 216 (0.4876 219 (0.4845)hCV27476043 RDH13 0.03332 16 (0.0362) 6 (0.0132) A G 109 (0.2466 125(0.2759) G G 317 (0.7172 322 (0.7108) (rs3745912) 0.04 16 (0.0362) 6(0.0132) A G 109 (0.2466 125 (0.2759) G G 317 (0.7172 322 (0.7108)hCV27937396 (rs4634201) 0.04871 25 (0.0567) 14 (0.031) C T 146 (0.3311140 (0.3097) T T 270 (0.6122 298 (0.6593) hCV2811695 FTO 0.00707 13(0.0294) 6 (0.0133) C A 106 (0.2398 83 (0.1844) A A 323 (0.7308 361(0.8022) (rs940214) 0.01189 13 (0.0294) 6 (0.0133) C A 106 (0.2398 83(0.1844) A A 323 (0.7308 361 (0.8022) 0.03143 13 (0.0294) 6 (0.0133) C A106 (0.2398 83 (0.1844) A A 323 (0.7308 361 (0.8022) hCV2852784 CYP17A10.01777 54 (0.1244) 73 (0.1648) G A 202 (0.4654 219 (0.4944) A A 178(0.4101 151 (0.3409) (rs743572) 0.0271 54 (0.1244) 73 (0.1648) G A 202(0.4654 219 (0.4944) A A 178 (0.4101 151 (0.3409) 0.03431 54 (0.1244) 73(0.1648) G A 202 (0.4654 219 (0.4944) A A 178 (0.4101 151 (0.3409)hCV2892855 FGG 0.00076 64 (0.1451) 87 (0.1925) T C 205 (0.4649 237(0.5243) C C 172 (0.39 128 (0.2832) (rs6536024) 0.0009 64 (0.1451) 87(0.1925) T C 205 (0.4649 237 (0.5243) C C 172 (0.39 128 (0.2832) 0.0028464 (0.1451) 87 (0.1925) T C 205 (0.4649 237 (0.5243) C C 172 (0.39 128(0.2832) hCV2892869 (rs13109457) 0.00029 58 (0.1315) 27 (0.0599) A G 187(0.424 196 (0.4346) G G 196 (0.4444 228 (0.5055) 0.00037 58 (0.1315) 27(0.0599) A G 187 (0.424 196 (0.4346) G G 196 (0.4444 228 (0.5055)0.00249 58 (0.1315) 27 (0.0599) A G 187 (0.424 196 (0.4346) G G 196(0.4444 228 (0.5055) hCV2892893 (rs12648258) 0.01399 31 (0.0703) 17(0.0376) A T 153 (0.3469 142 (0.3142) T T 257 (0.5828 293 (0.6482)0.01963 31 (0.0703) 17 (0.0376) A T 153 (0.3469 142 (0.3142) T T 257(0.5828 293 (0.6482) 0.033 31 (0.0703) 17 (0.0376) A T 153 (0.3469 142(0.3142) T T 257 (0.5828 293 (0.6482) 0.04454 31 (0.0703) 17 (0.0376) AT 153 (0.3469 142 (0.3142) T T 257 (0.5828 293 (0.6482) hCV2892905 PLRG10.03327 33 (0.0755) 21 (0.047) C T 156 (0.357 146 (0.3266) T T 248(0.5675 280 (0.6264) (rs12642770) 0.04994 33 (0.0755) 21 (0.047) C T 156(0.357 146 (0.3266) T T 248 (0.5675 280 (0.6264) hCV2892918 (rs12511469)0.02229 31 (0.0705) 18 (0.0399) A T 152 (0.3455 142 (0.3149) T T 257(0.5841 291 (0.6452) 0.03037 31 (0.0705) 18 (0.0399) A T 152 (0.3455 142(0.3149) T T 257 (0.5841 291 (0.6452) 0.04836 31 (0.0705) 18 (0.0399) AT 152 (0.3455 142 (0.3149) T T 257 (0.5841 291 (0.6452) hCV2892926(rs7662567) 0.00586 34(0.078) 18 (0.0399) C T 154 (0.3532 143 (0.3171) TT 248 (0.5688 290 (0.643) 0.00915 34 (0.078) 18 (0.0399) C T 154 (0.3532143 (0.3171) T T 248 (0.5688 290 (0.643) 0.01776 34 (0.078) 18 (0.0399)C T 154 (0.3532 143 (0.3171) T T 248 (0.5688 290 (0.643) 0.02387 34(0.078) 18 (0.0399) C T 154 (0.3532 143 (0.3171) T T 248 (0.5688 290(0.643) hCV2892927 (rs13123551) 0.01436 71 (0.1617) 85 (0.1881) T A 210(0.4784 239 (0.5288) A A 158 (0.3599 128 (0.2832) 0.02592 71 (0.1617) 85(0.1881) T A 210 (0.4784 239 (0.5288) A A 158 (0.3599 128 (0.2832)hCV29521317 LIMD1 0.02272 1 (0.0023) 0 (0) G A 60 (0.1357 41 (0.0907) AA 381 (0.862 411 (0.9093) (rs7648441) 0.02712 1 (0.0023) 0 (0) G A 60(0.1357 41 (0.0907) A A 381 (0.862 411 (0.9093) 0.03349 1 (0.0023) 0 (0)G A 60 (0.1357 41 (0.0907) A A 381 (0.862 411 (0.9093) hCV29983641(rs10008078) 0.00588 35 (0.0795) 17 (0.0379) A G 152 (0.3455 145(0.3229) G G 253 (0.575 287 (0.6392) 0.00921 35 (0.0795) 17 (0.0379) A G152 (0.3455 145 (0.3229) G G 253 (0.575 287 (0.6392) 0.00957 35 (0.0795)17 (0.0379) A G 152 (0.3455 145 (0.3229) G G 253 (0.575 287(0.6392)hCV30002208 (rs9402927) 0.04695 55 (0.1253) 78 (0.1729) G A 219 (0.4989211 (0.4678) A A 165 (0.3759 162 (0.3592) hCV30040828 TNFSF4 0.03454 5(0.0113) 4 (0.0089) T C 88 (0.1995 66 (0.147) C C 348 (0.7891 379(0.8441) (rs6700269) 0.03713 5 (0.0113) 4 (0.0089) T C 88 (0.1995 66(0.147) C C 348 (0.7891 379 (0.8441) 0.04223 5 (0.0113) 4 (0.0089) T C88 (0.1995 66 (0.147) C C 348 (0.7891 379 (0.8441) hCV30548253(rs9425773) 0.02996 7 (0.0159) 17 (0.0378) C A 113 (0.2568 99 (0.22) A A320 (0.7273 334 (0.7422) hCV305844 LOC728077 0.0275 86 (0.1941) 63(0.1391) C G 186 (0.4199 221 (0.4879) G G 171 (0.386 169 (0.3731)(rs4823562) hCV30711231 (rs12642469) 0.02106 32 (0.0724) 18 (0.0398) A G152 (0.3439 143 (0.3164) G G 258 (0.5837 291 (0.6438) 0.02334 32(0.0724) 18 (0.0398) A G 152 (0.3439 143 (0.3164) G G 258 (0.5837 291(0.6438) 0.03665 32 (0.0724) 18 (0.0398) A G 152 (0.3439 143 (0.3164) GG 258 (0.5837 291 (0.6438) hCV31475431 MMEL1 0.0372 6 (0.0135) 3(0.0066) T G 70 (0.158 100 (0.2208) G G 367 (0.8284) 350 (0.7726)(rs12133956) hCV31863982 (rs7659024) 2.2E−05 57 (0.129) 22 (0.0487) A G189 (0.4276 193 (0.427) G G 196 (0.4434 237 (0.5243) 4.6E−05 57 (0.129)22 (0.0487) A G 189 (0.4276 193 (0.427) G G 196 (0.4434 237 (0.5243)0.0002 57 (0.129) 22 (0.0487) A G 189 (0.4276 193 (0.427) G G 196(0.4434 237 (0.5243) 0.01564 57 (0.129) 22 (0.0487) A G 189 (0.4276 193(0.427) G G 196 (0.4434 237 (0.5243) hCV31965333 (rs10797390) 0.00973 76(0.1723) 105 (0.2323) T C 231 (0.5238 236 (0.5221) C C 134 (0.3039 111(0.2456) 0.01032 76 (0.1723) 105 (0.2323) T C 231 (0.5238 236 (0.5221) CC 134 (0.3039 111 (0.2456) 0.02629 76 (0.1723) 105 (0.2323) T C 231(0.5238 236 (0.5221) C C 134 (0.3039 111 (0.2456) hCV31997958 CHMP70.00266 81 (0.1837) 50 (0.1116) G A 201 (0.4558 215 (0.4799) A A 159(0.3605 183 (0.4085) (rs12544038) 0.00301 81 (0.1837) 50 (0.1116) G A201 (0.4558 215 (0.4799) A A 159 (0.3605 183 (0.4085) 0.00969 81(0.1837) 50 (0.1116) G A 201 (0.4558 215 (0.4799) A A 159 (0.3605 183(0.4085) hCV3205858 PXDNL 0.04375 76 (0.1716) 56 (0.1236) C T 196(0.4424 211 (0.4658) T T 171 (0.386 186 (0.4106) (rs2979122) hCV3210786C1orf164 0.00202 61 (0.138) 33 (0.0735) C T 177 (0.4005 200 (0.4454) T T204 (0.4615 216 (0.4811) (rs11582970) 0.00463 61 (0.138) 33 (0.0735) C T177 (0.4005 200 (0.4454) T T 204 (0.4615 216 (0.4811) hCV32212664(rs12642646) 0.00716 90 (0.2041) 96 (0.2124) G A 211 (0.4785 249(0.5509) A A 140 (0.3175 107 (0.2367) hCV7429782 FGG 0.01428 28 (0.0633)40 (0.0885) A T 175 (0.3959 203 (0.4491) T T 239 (0.5407 209 (0.4624)(rs1118823) 0.0193 28 (0.0633) 40 (0.0885) A T 175 (0.3959 203 (0.4491)T T 239 (0.5407 209 (0.4624) hCV7429793 (rs1025154) 0.01309 31 (0.0701)18 (0.0398) C T 157 (0.3552 143 (0.3164) T T 254 (0.5747 291 (0.6438)0.02761 31 (0.0701) 18 (0.0398) C T 157 (0.3552 143 (0.3164) T T 254(0.5747 291 (0.6438) 0.03429 31 (0.0701) 18 (0.0398) C T 157 (0.3552 143(0.3164) T T 254 (0.5747 291 (0.6438) 0.04931 31 (0.0701) 18 (0.0398) CT 157 (0.3552 143 (0.3164) T T 254 (0.5747 291 (0.6438) hCV788647(rs729045) 0.01217 56 (0.127) 82 (0.181) G A 227 (0.5147 234 (0.5166) AA 158 (0.3583 137 (0.3024) 0.01497 56 (0.127) 82 (0.181) G A 227 (0.5147234 (0.5166) A A 158 (0.3583 137 (0.3024) hCV813581 OR4C11 0.01556 21(0.0513) 10 (0.0233) T G 37 (0.0905 30 (0.0699) G G 351 (0.8582 389(0.9068) (rs491160) 0.02979 21 (0.0513) 10 (0.0233) T G 37 (0.0905 30(0.0699) G G 351 (0.8582 389 (0.9068) 0.03083 21 (0.0513) 10 (0.0233) TG 37 (0.0905 30 (0.0699) G G 351 (0.8582 389 (0.9068) 0.03607 21(0.0513) 10 (0.0233) T G 37 (0.0905 30 (0.0699) G G 351 (0.8582 389(0.9068) hCV8727391 C17orf81 0.01705 40 (0.0903) 63 (0.1394) G A 216(0.4876 199 (0.4403) A A 187 (0.4221 190 (0.4204) (rs414206) hCV8857351RGS7 0.03561 101 (0.229) 78 (0.1726) T C 210 (0.4762 228 (0.5044) C C130 (0.2948 146 (0.323) (rs2341021) hCV8911768 SERPINC1 0.01702 7(0.0159) 4 (0.0089) T C 92 (0.2091 69 (0.1533) C C 341 (0.775 377(0.8378) (rs941988) 0.02739 7 (0.0159) 4 (0.0089) T C 92 (0.2091 69(0.1533) C C 341 (0.775 377 (0.8378) hCV8919450 F5 (rs6017) 0.00317 26(0.0594) 31 (0.0692) G A 126 (0.2877 168 (0.375) A A 286 (0.653 249(0.5558) 0.00978 26 (0.0594) 31 (0.0692) G A 126 (0.2877 168 (0.375) A A286 (0.653 249 (0.5558) hCV8941510 CDSN 0.04988 16 (0.0364) 7 (0.0156) CA 118 (0.2682 113 (0.2511) A A 306 (0.6955 330 (0.7333) (rs1042127)hCV9114656 CFHR5 0.04258 5 (0.0113) 2 (0.0044) C T 76 (0.1723 60(0.1325) T T 360 (0.8163 391 (08631) (rs9427662) hCV9680592 MIPEP0.03902 34 (0.0769) 23 (0.0508) A G 149 (0.3371 184 (0.4062) G G 259(0.586 246 (0.543) (rs17079372) hDV70683187 (rs16846561) 0.02204 7(0.0159) 4 (0.0089) G C 95 (0.2159 73 (0.1622) C C 338 (0.7682 373(0.8289) 0.03622 7 (0.0159) 4 (0.0089) G C 95 (0.2159 73 (0.1622) C C338 (0.7682 373 (0.8289) hDV70683212 RC3H1 0.04442 3 (0.0068) 1 (0.0022)G C 72 (0.1633 55 (0.1222) C C 366 (0.8299 394 (0.8756) (rs16846593)hDV70683382 RABGAP1L 0.04002 4 (0.0091) 2 (0.0045) C G 59 (0.1338 42(0.094) G G 378 (0.8571 403 (0.9016) (rs16846815) hDV70965621(rs17534243) 0.0283 26 (0.059) 24 (0.0531) G A 173 (0.3923 147 (0.3252)A A 242 (0.5488 281 (0.6217)

TABLE 22 Table 22. Unadjusted association of 9 SNPs with DVT in MEGA-1(p <= 0.05) that have not been tested in LETS OR (95% Risk- NonRisk-marker annot P-value parameter Model CI) Allele Allele hCV11629656(rs17284) 0.000279 GG + GT_vs_TT dom 4.05 (1.9-8.61) G T 0.000997GT_vs_TT Gen 5.21 (1.95-13.91) G T 0.001553 G_vs_T add 2.44 (1.4-4.23) GT hCV11629657 (rs17286) 0.000274 AA + AG_vs_GG dom 4.06 (1.91-8.63) A G0.000984 AG_vs_GG Gen 5.22 (1.95-13.94) A G 0.001529 A_vs_G add 2.44(1.41-4.24) A G hCV11922386 MDM2 0.006966 CT_vs_TT Gen 3.34 (1.39-8.02)C T (rs1846401) 0.009319 CC + CT_vs_TT dom 2.73 (1.28-5.81) C T 0.03014C_vs_T add 1.96 (1.07-3.59) C T hCV1825046 PROCR 0.000399 T_vs_C add1.21 (1.09-1.34) T C (rs2069952) 0.000746 TT_vs_CC Gen 1.46 (1.17-1.82)T C 0.00224 TT_vs_TC + CC rec 1.26 (1.08-1.45) T C 0.006881 TT +TC_vs_CC dom 1.32 (1.08-1.62) T C hCV1841974 (rs1799809) 0.001032GG_vs_GA + AA rec 1.34 (1.12-1.59) G A 0.001263 GG_vs_AA Gen 1.39(1.14-1.7) G A 0.002126 G_vs_A add 1.17 (1.06-1.29) G A hCV2532034 F13B0.010904 CT_vs_TT Gen 1.28 (1.06-1.55) C T (rs6003) 0.01363 CC +CT_vs_TT dom 1.26 (1.05-1.52) C T 0.025493 C_vs_T add 1.21 (1.02-1.44) CT hCV25597241 AQP2 0.046904 A_vs_G add 1.19 (1-1.42) A G (rs3782320)hCV3170967 PLEKHA4 0.038558 CC_vs_CG + GG rec 1.27 (1.01-1.59) C G(rs556052) hDV71075942 (rs8176719) 3.47E−31 G_vs_T add  1.9 (1.71-2.12)G T 3.29E−30 GG + GT_vs_TT dom 2.48 (2.12-2.89) G T 1.26E−25 GG_vs_TTGen 3.32 (2.65-4.15) G T 8.35E−23 GT_vs_TT Gen 2.27 (1.93-2.67) G T3.19E−12 GG_vs_GT + TT rec 2.04 (1.67-2.49) G T Allele CONTROL cnt(CONTROL CASE cnt (CONTROL marker annot P-value frq) Genot (CASE frqfrq) Genot2 hCV11629656 (rs17284) 0.000279 G (0.0037 G G  8 (0.0059)  4(0.0023) G T 0.000997 G (0.0037 G G  8 (0.0059)  4 (0.0023) G T 0.001553G (0.0037 G G  8 (0.0059)  4 (0.0023) G T hCV11629657 (rs17286) 0.000274A (0.0037 A A  8 (0.0059)  4 (0.0023) A G 0.000984 A (0.0037 A A  8(0.0059)  4 (0.0023) A G 0.001529 A (0.0037 A A  8 (0.0059)  4 (0.0023)A G hCV11922386 MDM2 0.006966 C (0.0037 C C  3 (0.0022)  3 (0.0017) C T(rs1846401) 0.009319 C (0.0037 C C  3 (0.0022)  3 (0.0017) C T 0.03014 C(0.0037 C C  3 (0.0022)  3 (0.0017) C T hCV1825046 PROCR 0.000399 C(0.4011 C C 174 (0.1292) 288 (0.1641) C T (rs2069952) 0.000746 C (0.4011C C 174 (0.1292) 288 (0.1641) C T 0.00224 C (0.4011 C C 174 (0.1292) 288(0.1641) C T 0.006881 C (0.4011 C C 174 (0.1292) 288 (0.1641) C ThCV1841974 (rs1799809) 0.001032 G (0.4338 G G 317 (0.2348) 327 (0.1865)G A 0.001263 G (0.4338 G G 317 (0.2348) 327 (0.1865) G A 0.002126 G(0.4338 G G 317 (0.2348) 327 (0.1865) G A hCV2532034 F13B 0.010904 C(0.0896 C C  15 (0.0116)  20 (0.0118) C T (rs6003) 0.01363 C (0.0896 C C 15 (0.0116)  20 (0.0118) C T 0.025493 C (0.0896 C C  15 (0.0116)  20(0.0118) C T hCV25597241 AQP2 0.046904 A (0.083 A A  14 (0.0104)  13(0.0074) A G (rs3782320) hCV3170967 PLEKHA4 0.038558 C (0.3233 C C 169(0.1224) 173 (0.0991) C G (rs556052) hDV71075942 (rs8176719) 3.47E−31 G(0.3313 G G 272 (0.2022) 194 (0.1107) G T 3.29E−30 G (0.3313 G G 272(0.2022) 194 (0.1107) G T 1.26E−25 G (0.3313 G G 272 (0.2022) 194(0.1107) G T 8.35E−23 G (0.3313 G G 272 (0.2022) 194 (0.1107) G T3.19E−12 G (0.3313 G G 272 (0.2022) 194 (0.1107) G T CONTROL cnt CONTROLcnt CASE cnt (CONTROL CASE cnt (CONTROL marker annot P-value (CASE frq2frq)2 Genot3 (CASE frq3 frq)3 hCV11629656 (rs17284) 0.000279  20 (0.0146 5 (0.0029) T T 1339 (0.9795 1743 (0.9949) 0.000997  20 (0.0146  5(0.0029) T T 1339 (0.9795 1743 (0.9949) 0.001553  20 (0.0146  5 (0.0029)T T 1339 (0.9795 1743 (0.9949) hCV11629657 (rs17286) 0.000274  20(0.0146  5 (0.0029) G G 1338 (0.9795 1745 (0.9949) 0.000984  20 (0.0146 5 (0.0029) G G 1338 (0.9795 1745 (0.9949) 0.001529  20 (0.0146  5(0.0029) G G 1338 (0.9795 1745 (0.9949) hCV11922386 MDM2 0.006966  18(0.0132  7 (0.004) T T 1345 (0.9846 1747 (0.9943) (rs1846401) 0.009319 18 (0.0132  7 (0.004) T T 1345 (0.9846 1747 (0.9943) 0.03014  18(0.0132  7 (0.004) T T 1345 (0.9846 1747 (0.9943) hCV1825046 PROCR0.000399 613 (0.4551 832 (0.4741) T T  560 (0.4157  635 (0.3618)(rs2069952) 0.000746 613 (0.4551 832 (0.4741) T T  560 (0.4157  635(0.3618) 0.00224 613 (0.4551 832 (0.4741) T T  560 (0.4157  635 (0.3618)0.006881 613 (0.4551 832 (0.4741) T T  560 (0.4157  635 (0.3618)hCV1841974 (rs1799809) 0.001032 644 (0.477  867 (0.4946) A A  389(0.2881  559 (0.3189) 0.001263 644 (0.477  867 (0.4946) A A  389 (0.2881 559 (0.3189) 0.002126 644 (0.477  867 (0.4946) A A  389 (0.2881  559(0.3189) hCV2532034 F13B 0.010904 248 (0.1911 265 (0.1557) T T 1035(0.7974 1417 (0.8325) (rs6003) 0.01363 248 (0.1911 265 (0.1557) T T 1035(0.7974 1417 (0.8325) 0.025493 248 (0.1911 265 (0.1557) T T 1035 (0.79741417 (0.8325) hCV25597241 AQP2 0.046904 235 (0.1743 265 (0.1511) G G1099 (0.8153 1476 (0.8415) (rs3782320) hCV3170967 PLEKHA4 0.038558 579(0.4193 783 (0.4485) G G  633 (0.4584  790 (0.4525) (rs556052)hDV71075942 (rs8176719) 3.47E−31 741 (0.5509 773 (0.4412) T T  332(0.2468  785 (0.4481) 3.29E−30 741 (0.5509 773 (0.4412) T T  332 (0.2468 785 (0.4481) 1.26E−25 741 (0.5509 773 (0.4412) T T  332 (0.2468  785(0.4481) 8.35E−23 741 (0.5509 773 (0.4412) T T  332 (0.2468  785(0.4481) 3.19E−12 741 (0.5509 773 (0.4412) T T  332 (0.2468  785(0.4481)

TABLE 23 Table 23. Age- and sex-adjusted association of 41 SNPs with DVTin LETS, MEGA-1, and MEGA-2 Gene Ref- NonRef- Risk Control P- Case CaseMarker Symbol RS number Allele Allele Allele Stratum RAF Model Parametervalue OddsRatio OR95l OR95u Genot Count3 Freq3 hCV11503414 FGG rs2066865G A A LETS 0.263982 additive hCV11503414.AA.AG.adtv 5E−04 1.448 1.177341.780951 GG 195 0.45 MEGA-1 0.274644 additive hCV11503414.AA.AG.adtv9E−10 1.4046 1.25977 1.566181 GG 574 0.43 MEGA-2 0.260379 additivehCV11503414.AA.AG.adtv 1E−08 1.352 1.21875 1.499831 GG 577 0.46hCV11503469 FGG rs2066854 T A A LETS 0.259382 additivehCV11503469.AA.AT.adtv 2E−04 1.4852 1.20554 1.829853 TT 196 0.44 MEGA-10.275242 additive hCV11503469.AA.AT.adtv 7E−10 1.402 1.25909 1.561084 TT593 0.43 MEGA-2 0.261723 additive hCV11503469.AA.AT.adtv 2E−08 1.34591.21349 1.492657 TT 577 0.46 hCV11503470 rs1800788 C T T LETS 0.196903additive hCV11503470.TT.TC.adtv 0.014 1.3226 1.0586 1.652468 CC 256 0.58MEGA-1 0.216448 additive hCV11503470.TT.TC.adtv 0.008 1.1694 1.041761.312675 CC 790 0.57 MEGA-2 0.202849 additive hCV11503470.TT.TC.adtv2E−04 1.236 1.10482 1.382765 CC 731 0.58 hCV11975250 F5 rs6025 C T TLETS 0.015487 additive hCV11975250.TT.TC.adtv 2E−11 7.1787 4.0420712.7492 CC 354 0.8 MEGA-1 0.027335 additive hCV11975250.TT.TC.adtv 1E−304.0963 3.22255 5.207016 CC 1120 0.8 MEGA-2 0.025825 additivehCV11975250.TT.TC.adtv 1E−39 4.273 3.44263 5.30362 CC 1029 0.81hCV12066124 F11 rs2036914 C T C LETS 0.543046 additivehCV12066124.TT.TC.adtv 0.013 0.7892 0.65464 0.951525 CC 159 0.36 MEGA-10.521677 additive hCV12066124.TT.TC.adtv 2E−07 0.7657 0.69212 0.846995CC 476 0.34 MEGA-2 0.51645 additive hCV12066124.TT.TC.adtv 7E−12 0.71380.64823 0.786089 CC 445 0.36 hCV15860433 rs2070006 C T T LETS 0.401111additive hCV15860433.TT.TC.adtv 0.024 1.241 1.02908 1.496544 CC 135 0.31MEGA-1 0.406963 additive hCV15860433.TT.TC.adtv 4E−05 1.2352 1.117091.365809 CC 405 0.29 MEGA-2 0.388687 additive hCV15860433.TT.TC.adtv2E−06 1.2603 1.14598 1.386016 CC 390 0.31 hCV16180170 SERPINC1 rs2227589C T T LETS 0.086283 additive hCV16180170.TT.TC.adtv 0.026 1.421 1.043061.935767 CC 344 0.78 MEGA-1 0.089174 additive hCV16180170.TT.TC.adtv0.009 1.2448 1.05553 1.4679 CC 1109 0.8 MEGA-2 0.095028 additivehCV16180170.TT.TC.adtv 9E−04 1.2863 1.10835 1.49275 CC 1001 0.77hCV233148 KT3/SDCCAG rs1417121 G C C LETS 0.262693 additivehCV233148.CC.CG.adtv 3E−04 1.4537 1.18416 1.78458 GG 191 0.43 MEGA-10.285592 additive hCV233148.CC.CG.adtv 0.001 1.1955 1.07302 1.332 GG 6520.47 MEGA-2 0.273489 additive hCV233148.CC.CG.adtv 0.018 1.1326 1.021891.255409 GG 626 0.5 hCV25990131 CYP4V2 rs13146272 A C A LETS 0.649007additive hCV25990131.CC.CA.adtv 0.048 0.8182 0.67063 0.998308 AA 2020.46 MEGA-1 0.640046 additive hCV25990131.CC.CA.adtv 0.001 0.84340.75935 0.936754 AA 648 0.46 MEGA-2 0.641387 additivehCV25990131.CC.CA.adtv 6E−05 0.8101 0.73057 0.898278 AA 561 0.48hCV27474895 F11 rs3756011 C A A LETS 0.424779 additivehCV27474895.AA.AC.adtv 0.035 1.2135 1.01344 1.452968 CC 128 0.29 MEGA-10.418432 additive hCV27474895.AA.AC.adtv 4E−08 1.3273 1.19988 1.468181CC 361 0.26 MEGA-2 0.396894 additive hCV27474895.AA.AC.adtv 2E−12 1.40431.27743 1.543811 CC 342 0.27 hCV27477533 F11 rs3756008 A T T LETS0.415929 additive hCV27477533.TT.TA.adtv 0.031 1.2211 1.01816 1.464466AA 129 0.29 MEGA-1 0.406625 additive hCV27477533.TT.TA.adtv 9E−07 1.2861.16309 1.42186 AA 397 0.28 MEGA-2 0.388969 additivehCV27477533.TT.TA.adtv 2E−12 1.4088 1.28095 1.549479 AA 346 0.28hCV8241630 F11 rs925451 G A A LETS 0.40708 additivehCV8241630.AA.AG.adtv 0.046 1.2036 1.00372 1.443218 GG 134 0.3 MEGA-10.388794 additive hCV8241630.AA.AG.adtv 4E−08 1.3296 1.20124 1.471753 GG403 0.3 MEGA-2 0.373285 additive hCV8241630.AA.AG.adtv 1E−11 1.38791.26191 1.526573 GG 374 0.3 hCV8717873 GP6/RDH13 rs1613662 A G A LETS0.800221 additive hCV8717873.GG.GA.adtv 0.013 0.7329 0.57372 0.936291 AA316 0.71 MEGA-1 0.807033 additive hCV8717873.GG.GA.adtv 0.004 0.82490.72386 0.940033 AA 975 0.7 MEGA-2 0.822156 additivehCV8717873.GG.GA.adtv 0.031 0.8709 0.76791 0.987716 AA 915 0.7hCV8726802 F2 rs1799963 G A A LETS 0.011111 additivehCV8726802.AA.AG.adtv 0.004 2.99 1.43284 6.239603 GG 414 0.94 MEGA-10.010559 additive hCV8726802.AA.AG.adtv 2E−07 2.8476 1.91526 4.233889 GG1301 0.94 MEGA-2 0.009653 additive hCV8726802.AA.AG.adtv 1E−10 3.20962.25263 4.57324 GG 1219 0.94 hCV8919444 F5 rs4524 T C T LETS 0.742257additive hCV8919444.CC.CT.adtv 0.006 0.7351 0.5915 0.913666 TT 289 0.65MEGA-1 0.744717 additive hCV8919444.CC.CT.adtv 1E−04 0.793 0.704490.892524 TT 872 0.63 MEGA-2 0.7332 additive hCV8919444.CC.CT.adtv 6E−070.7525 0.67308 0.841315 TT 773 0.62 hCV15949414 XYLB rs2234628 G A GLETS 0.94308 dominant hCV15949414.GG.dom 0.036 0.6085 0.38271 0.967377GG 409 0.93 MEGA-1 0.950371 dominant hCV15949414.GG.dom 0.003 0.67540.51964 0.87772 GG 1269 0.93 MEGA-2 0.946416 dominant hCV15949414.GG.dom0.025 0.7617 0.6 0.966871 GG 1152 0.92 hCV15968043 CYP4V2 rs2292423 T AA LETS 0.432671 dominant hCV15968043.TT.dom 0.043 1.3422 1.00887 1.7856TT 122 0.28 MEGA-1 0.412794 dominant hCV15968043.TT.dom 2E−04 1.33781.14802 1.559058 TT 395 0.29 MEGA-2 0.406888 dominant hCV15968043.TT.dom7E−07 1.4572 1.25589 1.690689 TT 330 0.27 hCV263841 NR1I2 rs1523127 A CC LETS 0.331126 recessive hCV263841.CC.rec 2E−04 1.9998 1.38179 2.894094AA 160 0.36 MEGA-1 0.391106 recessive hCV263841.CC.rec 0.018 1.25691.03941 1.52002 AA 462 0.33 MEGA-2 0.379129 recessive hCV263841.CC.rec0.027 1.2241 1.02327 1.464342 AA 480 0.37 hCV916107 RGS7 rs670659 C T CLETS 0.644592 recessive hCV916107.TT.rec 0.048 0.6546 0.43 0.99638 CC216 0.49 MEGA-1 0.643021 recessive hCV916107.TT.rec 0.012 0.755 0.606840.939319 CC 622 0.45 MEGA-2 0.64079 recessive hCV916107.TT.rec 0.0210.778 0.62855 0.963064 CC 548 0.42 hCV1841975 PROC rs1799810 A T T LETS0.426991 additive hCV1841975.TT.TA.adtv 0.074 1.1855 0.98365 1.428736 AA127 0.29 MEGA-1 0.435604 additive hCV1841975.TT.TA.adtv 0.01 1.13881.03113 1.257773 AA 410 0.3 MEGA-2 0.428546 additivehCV1841975.TT.TA.adtv 7E−04 1.1795 1.07246 1.297319 AA 336 0.27hCV25474413 F11 rs3822057 C A C LETS 0.50883 additivehCV25474413.AA.AC.adtv 0.066 0.8427 0.70217 1.011372 CC 138 0.31 MEGA-10.490023 additive hCV25474413.AA.AC.adtv 2E−06 0.7817 0.70639 0.865066CC 406 0.3 MEGA-2 0.479993 additive hCV25474413.AA.AC.adtv 2E−10 0.73570.66925 0.808801 CC 391 0.31 hCV2892877 FGA rs6050 T C C LETS 0.249448additive hCV2892877.CC.CT.adtv 0.058 1.2897 0.9909 1.678671 TT 194 0.44MEGA-1 0.245709 additive hCV2892877.CC.CT.adtv 7E−07 1.4325 1.242721.651308 TT 581 0.42 MEGA-2 0.230097 additive hCV2892877.CC.CT.adtv2E−04 1.3033 1.13392 1.498055 TT 510 0.48 hCV3230038 F11 rs2289252 C T TLETS 0.427938 additive hCV3230038.TT.TC.adtv 0.062 1.187 0.991741.420769 CC 130 0.29 MEGA-1 0.41681 additive hCV3230038.TT.TC.adtv 9E−091.3489 1.21786 1.493929 CC 344 0.26 MEGA-2 0.395638 additivehCV3230038.TT.TC.adtv 2E−12 1.4074 1.28018 1.547352 CC 343 0.27hCV596331 F9 rs6048 A G A LETS 0.673289 additive hCV596331.GG.GA.adtv0.026 0.8222 0.69227 0.976638 AA 274 0.62 MEGA-1 0.69609 additivehCV596331.GG.GA.adtv 0.065 0.9185 0.83911 1.005393 AA 844 0.62 MEGA-20.699614 additive hCV596331.GG.GA.adtv 0.094 0.9302 0.85473 1.012392 AA797 0.61 hCV11786258 KLKB1 rs4253303 G A A LETS 0.415929 dominanthCV11786258.GG.dom 0.09 1.2752 0.96283 1.688914 GG 132 0.3 MEGA-10.39355 dominant hCV11786258.GG.dom 2E−04 1.3243 1.14055 1.537568 GG 4340.31 MEGA-2 0.392883 dominant hCV11786258.GG.dom 7E−06 1.3922 1.204831.608816 GG 364 0.29 hCV3230096 CYP4V2 rs3817184 C T T LETS 0.436947dominant hCV3230096.CC.dom 0.056 1.3236 0.99247 1.765259 CC 120 0.27MEGA-1 0.416379 dominant hCV3230096.CC.dom 0.002 1.2697 1.09046 1.478413CC 409 0.29 MEGA-2 0.414836 dominant hCV3230096.CC.dom 6E−06 1.40431.21187 1.627272 CC 338 0.27 hCV11541681 NAT8B rs2001490 G C C LETS0.384106 recessive hCV11541681.CC.rec 0.038 1.4687 1.02118 2.112445 GG142 0.32 MEGA-1 0.370296 recessive hCV11541681.CC.rec 0.046 1.22111.00323 1.486365 GG 502 0.36 MEGA-2 0.372281 recessivehCV11541681.CC.rec 0.093 1.17 0.97407 1.405291 GG 490 0.38 hCV1859855GOLGA3/POL rs2291260 T C C LETS 0.193157 recessive hCV1859855.CC.rec0.234 1.4721 0.7791 2.78168 TT 269 0.61 MEGA-1 0.219714 recessivehCV1859855.CC.rec 2E−04 1.8088 1.32175 2.475445 TT 797 0.58 MEGA-20.217825 recessive hCV1859855.CC.rec 0.035 1.3716 1.0217 1.841426 TT 7430.58 hCV1874482 ZDHHC6 rs2306158 G A G LETS 0.603563 recessivehCV1874482.AA.rec 0.029 0.6576 0.45097 0.958845 GG 197 0.45 MEGA-10.637435 recessive hCV1874482.AA.rec 0.901 0.9863 0.79453 1.224375 GG570 0.41 MEGA-2 0.640047 recessive 482.AA.re 0.044 0.8014 0.645830.994348 GG 462 0.43 hCV15793897 KLKB1 rs3087505 G A G LETS 0.899113additive hCV15793897.AA.AG.adtv 0.172 0.7939 0.56997 1.105919 GG 3700.84 MEGA-1 0.88683 additive hCV15793897.AA.AG.adtv 0.006 0.7891 0.666960.933557 GG 1139 0.82 MEGA-2 0.889009 additive hCV15793897.AA.AG.adtv9E−04 0.7628 0.65053 0.894335 GG 1050 0.84 hCV15871021 EBF1 rs2072495 GA G LETS 0.591611 additive hCV15871021.AA.AG.adtv 0.142 0.8667 0.716011.049207 GG 181 0.41 MEGA-1 0.607102 additive hCV15871021.AA.AG.adtv0.074 0.9092 0.81901 1.009384 GG 526 0.38 MEGA-2 0.605159 additivehCV15871021.AA.AG.adtv 0.073 0.9144 0.82917 1.008452 GG 490 0.39hCV22272267 KLKB1 rs3733402 A G A LETS 0.548673 additivehCV22272267.GG.GA.adtv 0.669 0.9604 0.79793 1.155992 AA 142 0.32 MEGA-10.509703 additive hCV22272267.GG.GA.adtv 2E−06 0.7815 0.70564 0.865522AA 444 0.32 MEGA-2 0.515971 additive hCV22272267.GG.GA.adtv 4E−06 0.79750.72433 0.877967 AA 389 0.31 hCV2303891 APOH rs1801690 C G C LETS0.948775 additive hCV2303891.GG.GC.adtv 0.043 0.6069 0.37388 0.984984 CC411 0.94 MEGA-1 0.94302 dominant hCV2303891.CC.dom 0.002 0.6822 0.533840.871787 CC 1285 0.92 MEGA-2 0.946824 dominant hCV2303891.CC.dom 0.1310.8388 0.66754 1.053943 CC 1140 0.91 hCV25620145 PROCR rs867186 A G GLETS 0.124169 additive hCV25620145.GG.GA.adtv 0.112 1.2446 0.95051.62976 AA 320 0.72 MEGA-1 0.122222 additive hCV25620145.GG.GA.adtv0.012 1.2067 1.04274 1.396475 AA 1018 0.73 MEGA-2 0.12575 additivehCV25620145.GG.GA.adtv 0.068 1.1355 0.99044 1.301869 AA 960 0.74hCV8827309 SUMF1 rs1110796 C T T LETS 0.102876 additivehCV8827309.TT.TC.adtv 0.005 1.4964 1.12625 1.988271 CC 321 0.73 MEGA-10.12044 additive hCV8827309.TT.TC.adtv 0.04 1.1711 1.00737 1.361357 CC1022 0.74 MEGA-2 0.124954 recessive hCV8827309.TT.rec 0.075 1.51070.95904 2.37983 CC 947 0.76 hCV8957432 RAC2 rs6572 G C C LETS 0.445796recessive hCV8957432.CC.rec 0.043 1.409 1.01101 1.963723 GG 117 0.27MEGA-1 0.436395 recessive hCV8957432.CC.rec 0.034 1.207 1.01423 1.436506GG 405 0.29 MEGA-2 0.448227 dominant hCV8957432.GG.dom 0.093 1.13180.97954 1.307629 GG 369 0.28 hCV2086329 SPARC rs4958487 A G A MEGA-20.555135 recessive hCV2086329.GG.rec 0.045 0.8386 0.70592 0.996203 AA394 0.31 G LETS 0.418322 recessive hCV2086329.GG.rec 0.013 1.52011.09176 2.116484 AA 134 0.3 MEGA-1 0.421848 recessive hCV2086329.GG.rec0.001 1.3419 1.12173 1.605263 AA 456 0.33 hCV25768636 $$CDC36/USP1rs4279134 G A A LETS 0.327051 recessive hCV25768636.AA.rec 0.035 1.52941.02978 2.271413 GG 177 0.4 MEGA-1 0.344641 recessive hCV25768636.AA.rec0.037 1.256 1.01355 1.556464 GG 559 0.4 G MEGA-2 0.644432 recessivehCV25768636.AA.rec 0.042 0.8065 0.65574 0.991971 GG 581 0.46 hCV29821005LOC728284 rs6552970 C T C MEGA-2 0.845877 additivehCV29821005.TT.TC.adtv 0.003 0.8107 0.70689 0.929688 CC 912 0.78 T LETS0.205556 additive hCV29821005.TT.TC.adtv 0.089 1.2192 0.97054 1.531643CC 250 0.57 MEGA-1 0.194413 additive hCV29821005.TT.TC.adtv 0.025 1.15111.01771 1.302014 CC 820 0.61 hCV31199195 KCTD10 rs10850234 A C A MEGA-20.829957 dominant hCV31199195.AA.dom 0.08 0.8767 0.75671 1.015687 AA 8960.72 C LETS 0.153422 dominant hCV31199195.AA.dom 0.019 1.4068 1.057681.871125 AA 289 0.65 MEGA-1 0.168379 dominant hCV31199195.AA.dom 0.0451.1666 1.00343 1.356282 AA 913 0.66 hCV11975651 SERPINC1 rs677 C G CLETS 0.890244 recessive hCV11975651.GG.rec 0.048 0.274 0.07591 0.98926CC 342 0.78 C MEGA-2 0.873245 additive hCV11975651.GG.GC.adtv 0.0410.8568 0.7386 0.99401 CC 990 0.79 G LETS 0.109756 general hCV11975651.GC0.1 1.324 0.94755 1.850018 CC 342 0.78 Gene Ref- NonRef- Risk Control-Control Case Case Control- Countrol- Case- Case Control- Control- MarkerSymbol RS number Allele Allele Allele Stratum Count3 Freq3 Genot2 Count4Freq4 Count4 Freq4 Genot3 Count5 Freq5 Count5 Freq5 hCV11503414 FGGrs2066865 G A A LETS 235 0.5 AG 186 0.426 188 0.42 AA 56 0.13 24 0.054MEGA-1 927 0.5 AG 608 0.451 692 0.39 AA 166 0.12 136 0.077 MEGA-2 14990.5 AG 536 0.43 1064 0.39 AA 134 0.11 183 0.067 hCV11503469 FGGrs2066854 T A A LETS 240 0.5 AT 192 0.434 191 0.42 AA 54 0.12 22 0.049MEGA-1 927 0.5 AT 624 0.449 687 0.39 AA 174 0.13 139 0.079 MEGA-2 14960.5 AT 530 0.426 1070 0.39 AA 137 0.11 185 0.067 hCV11503470 rs1800788 CT T LETS 291 0.6 TC 156 0.352 144 0.32 TT 31 0.07 17 0.038 MEGA-1 11000.6 TC 512 0.369 544 0.31 TT 85 0.06 107 0.061 MEGA-2 1764 0.6 TC 4450.355 893 0.32 TT 78 0.06 116 0.042 hCV11975250 F5 rs6025 C T T LETS 4381 TC 78 0.177 14 0.03 TT 8 0.02 0 0 MEGA-1 1665 0.9 TC 265 0.19 86 0.05TT 13 0.01 5 0.003 MEGA-2 2646 0.9 TC 235 0.185 140 0.05 TT 8 0.01 27E−04 hCV12066124 F11 rs2036914 C T C LETS 138 0.3 TC 215 0.485 216 0.48TT 69 0.16 99 0.219 MEGA-1 482 0.3 TC 682 0.49 865 0.49 TT 233 0.17 4060.232 MEGA-2 744 0.3 TC 602 0.484 1369 0.49 TT 197 0.16 653 0.236hCV15860433 rs2070006 C T T LETS 161 0.4 TC 211 0.478 217 0.48 TT 950.22 72 0.16 MEGA-1 623 0.4 TC 689 0.496 832 0.47 TT 296 0.21 297 0.17MEGA-2 1042 0.4 TC 603 0.483 1288 0.47 TT 255 0.2 428 0.155 hCV16180170SERPINC1 rs2227589 C T T LETS 378 0.8 TC 93 0.21 70 0.15 TT 6 0.01 40.009 MEGA-1 1457 0.8 TC 259 0.186 283 0.16 TT 22 0.02 15 0.009 MEGA-22325 0.8 TC 278 0.215 483 0.17 TT 15 0.01 28 0.01 hCV233148 KT3/SDCCAGrs1417121 G C C LETS 247 0.5 CG 202 0.456 174 0.38 CC 50 0.11 32 0.071MEGA-1 882 0.5 CG 573 0.413 745 0.42 CC 163 0.12 129 0.073 MEGA-2 14580.5 CG 494 0.396 1074 0.39 CC 126 0.1 214 0.078 hCV25990131 CYP4V2rs13146272 A C A LETS 199 0.4 CA 207 0.469 190 0.42 CC 32 0.07 64 0.141MEGA-1 720 0.4 CA 600 0.429 804 0.46 CC 149 0.11 229 0.131 MEGA-2 10940.4 CA 478 0.412 1178 0.45 CC 121 0.1 352 0.134 hCV27474895 F11rs3756011 C A A LETS 160 0.4 AC 208 0.47 200 0.44 AA 107 0.24 92 0.204MEGA-1 597 0.3 AC 692 0.502 838 0.48 AA 326 0.24 312 0.179 MEGA-2 10220.4 AC 612 0.489 1296 0.47 AA 297 0.24 451 0.163 hCV27477533 F11rs3756008 A T T LETS 164 0.4 TA 212 0.48 200 0.44 TT 101 0.23 88 0.195MEGA-1 623 0.4 TA 691 0.495 832 0.48 TT 307 0.22 296 0.169 MEGA-2 10480.4 TA 619 0.496 1283 0.46 TT 282 0.23 434 0.157 hCV8241630 F11 rs925451G A A LETS 171 0.4 AG 212 0.481 194 0.43 AA 95 0.22 87 0.192 MEGA-1 6610.4 AG 666 0.49 816 0.47 AA 289 0.21 272 0.156 MEGA-2 1107 0.4 AG 6220.496 1258 0.45 AA 259 0.21 405 0.146 hCV8717873 GP6/RDH13 rs1613662 A GA LETS 291 0.6 GA 117 0.264 143 0.32 GG 10 0.02 19 0.042 MEGA-1 1135 0.6GA 368 0.265 553 0.32 GG 45 0.03 61 0.035 MEGA-2 1924 0.7 GA 355 0.273835 0.29 GG 29 0.02 89 0.031 hCV8726802 F2 rs1799963 G A A LETS 440 1 AG28 0.063 10 0.02 AA 0 0 0 0 MEGA-1 1715 1 AG 80 0.058 37 0.02 AA 0 0 0 0MEGA-2 2794 1 AG 76 0.059 55 0.02 AA 0 0 0 0 hCV8919444 F5 rs4524 T C TLETS 251 0.6 CT 130 0.293 169 0.37 CC 24 0.05 32 0.071 MEGA-1 964 0.6 CT440 0.317 680 0.39 CC 76 0.05 107 0.061 MEGA-2 1502 0.5 CT 415 0.3331033 0.38 CC 59 0.05 218 0.079 hCV15949414 XYLB rs2234628 G A G LETS 3970.9 AG 31 0.07 51 0.11 AA 1 0 0 0 MEGA-1 1580 0.9 AG 89 0.065 172 0.1 AA5 0 1 6E−04 MEGA-2 2479 0.9 AG 98 0.078 270 0.1 AA 2 0 13 0.005hCV15968043 CYP4V2 rs2292423 T A A LETS 153 0.3 AT 224 0.506 208 0.46 AA97 0.22 92 0.203 MEGA-1 604 0.3 AT 698 0.504 839 0.48 AA 292 0.21 3000.172 MEGA-2 958 0.3 AT 632 0.515 1339 0.49 AA 264 0.22 447 0.163hCV263841 NR1I2 rs1523127 A C C LETS 205 0.5 CA 191 0.432 196 0.43 CC 910.21 52 0.115 MEGA-1 643 0.4 CA 684 0.49 850 0.48 CC 250 0.18 261 0.149MEGA-2 1097 0.4 CA 598 0.461 1340 0.47 CC 220 0.17 409 0.144 hCV916107RGS7 rs670659 C T C LETS 192 0.4 TC 185 0.419 200 0.44 TT 41 0.09 610.135 MEGA-1 738 0.4 TC 620 0.446 772 0.44 TT 149 0.11 238 0.136 MEGA-21153 0.4 TC 615 0.476 1326 0.47 TT 129 0.1 355 0.125 hCV1841975 PROCrs1799810 A T T LETS 147 0.3 TA 215 0.486 224 0.5 TT 100 0.23 81 0.179MEGA-1 554 0.3 TA 655 0.472 864 0.49 TT 323 0.23 329 0.188 MEGA-2 9180.3 TA 654 0.524 1331 0.48 TT 259 0.21 522 0.188 hCV25474413 F11rs3822057 C A C LETS 124 0.3 AC 214 0.483 213 0.47 AA 91 0.21 116 0.256MEGA-1 422 0.2 AC 690 0.505 875 0.5 AA 269 0.2 457 0.261 MEGA-2 650 0.2AC 617 0.492 1363 0.49 AA 247 0.2 761 0.274 hCV2892877 FGA rs6050 T C CLETS 227 0.5 CT 249 0.562 226 0.5 CC 0 0 0 0 MEGA-1 889 0.5 CT 807 0.581859 0.49 CC 0 0 0 0 MEGA-2 1348 0.5 CT 554 0.517 1095 0.44 CC 7 0.01 190.008 hCV3230038 F11 rs2289252 C T T LETS 158 0.4 TC 204 0.463 200 0.44TT 107 0.24 93 0.206 MEGA-1 600 0.3 TC 689 0.512 840 0.48 TT 314 0.23309 0.177 MEGA-2 1026 0.4 TC 618 0.492 1301 0.47 TT 295 0.23 447 0.161hCV596331 F9 rs6048 A G A LETS 244 0.5 GA 99 0.223 122 0.27 GG 70 0.1687 0.192 MEGA-1 1037 0.6 GA 295 0.215 347 0.2 GG 233 0.17 355 0.204MEGA-2 1682 0.6 GA 278 0.214 621 0.22 GG 222 0.17 545 0.191 hCV11786258KLKB1 rs4253303 G A A LETS 159 0.4 AG 227 0.514 210 0.46 AA 83 0.19 830.184 MEGA-1 655 0.4 AG 686 0.493 815 0.47 AA 271 0.19 282 0.161 MEGA-21007 0.4 AG 628 0.503 1347 0.49 AA 257 0.21 414 0.15 hCV3230096 CYP4V2rs3817184 C T T LETS 149 0.3 TC 227 0.514 211 0.47 TT 95 0.21 92 0.204MEGA-1 600 0.3 TC 680 0.489 831 0.48 TT 301 0.22 309 0.178 MEGA-2 9460.3 TC 636 0.506 1358 0.49 TT 282 0.22 473 0.17 hCV11541681 NAT8Brs2001490 G C C LETS 165 0.4 CG 220 0.497 228 0.5 CC 81 0.18 60 0.132MEGA-1 697 0.4 CG 662 0.476 815 0.46 CC 228 0.16 242 0.138 MEGA-2 11220.4 CG 603 0.465 1334 0.47 CC 205 0.16 394 0.138 hCV1859855 GOLGA3/POLrs2291260 T C C LETS 295 0.7 CT 148 0.336 141 0.31 CC 24 0.05 17 0.038MEGA-1 1052 0.6 CT 485 0.351 627 0.36 CC 99 0.07 71 0.041 MEGA-2 17050.6 CT 469 0.364 978 0.35 CC 76 0.06 122 0.043 hCV1874482 ZDHHC6rs2306158 G A G LETS 171 0.4 AG 187 0.428 200 0.45 AA 53 0.12 78 0.174MEGA-1 692 0.4 AG 641 0.465 833 0.48 AA 167 0.12 214 0.123 MEGA-2 9210.4 AG 485 0.448 891 0.42 AA 135 0.12 323 0.151 hCV15793897 KLKB1rs3087505 G A G LETS 363 0.8 AG 71 0.161 85 0.19 AA 1 0 3 0.007 MEGA-11379 0.8 AG 246 0.177 353 0.2 AA 5 0 22 0.013 MEGA-2 2206 0.8 AG 1930.154 506 0.18 AA 11 0.01 54 0.02 hCV15871021 EBF1 rs2072495 G A G LETS149 0.3 AG 191 0.432 238 0.53 AA 70 0.16 66 0.146 MEGA-1 643 0.4 AG 6990.502 834 0.48 AA 168 0.12 269 0.154 MEGA-2 1004 0.4 AG 592 0.471 13470.49 AA 174 0.14 421 0.152 hCV22272267 KLKB1 rs3733402 A G A LETS 1350.3 GA 210 0.475 226 0.5 GG 90 0.2 91 0.201 MEGA-1 437 0.2 GA 692 0.498912 0.52 GG 254 0.18 403 0.23 MEGA-2 741 0.3 GA 638 0.515 1361 0.49 GG212 0.17 653 0.237 hCV2303891 APOH rs1801690 C G C LETS 404 0.9 GC 280.064 44 0.1 GG 0 0 1 0.002 MEGA-1 1559 0.9 GC 106 0.076 192 0.11 GG 4 04 0.002 MEGA-2 2464 0.9 GC 109 0.087 289 0.1 GG 4 0 2 7E−04 hCV25620145PROCR rs867186 A G G LETS 347 0.8 GA 113 0.255 96 0.21 GG 10 0.02 80.018 MEGA-1 1354 0.8 GA 340 0.245 373 0.21 GG 30 0.02 28 0.016 MEGA-22160 0.8 GA 310 0.239 637 0.22 GG 27 0.02 38 0.013 hCV8827309 SUMF1rs1110796 C T T LETS 364 0.8 TC 107 0.244 83 0.18 TT 11 0.03 5 0.011MEGA-1 1335 0.8 TC 339 0.245 368 0.21 TT 21 0.02 24 0.014 MEGA-2 21030.8 TC 266 0.214 591 0.22 TT 32 0.03 47 0.017 hCV8957432 RAC2 rs6572 G CC LETS 126 0.3 CG 225 0.51 249 0.55 CC 99 0.22 77 0.17 MEGA-1 557 0.3 CG676 0.487 862 0.49 CC 308 0.22 334 0.191 MEGA-2 882 0.3 CG 665 0.5121380 0.48 CC 265 0.2 587 0.206 hCV2086329 SPARC rs4958487 A G A MEGA-2870 0.3 GA 641 0.51 1341 0.48 GG 221 0.18 564 0.203 G LETS 150 0.3 GA205 0.463 227 0.5 GG 104 0.23 76 0.168 MEGA-1 570 0.3 GA 631 0.456 8870.51 GG 298 0.22 296 0.169 hCV25768636 $$CDC36/USP1 rs4279134 G A A LETS204 0.5 AG 197 0.446 199 0.44 AA 68 0.15 48 0.106 MEGA-1 739 0.4 AG 6390.461 821 0.47 AA 188 0.14 194 0.111 G MEGA-2 1171 0.4 AG 535 0.426 12230.44 AA 140 0.11 372 0.134 hCV29821005 LOC728284 rs6552970 C T C MEGA-21919 0.7 TC 220 0.188 635 0.24 TT 38 0.03 90 0.034 T LETS 284 0.6 TC 1700.386 147 0.33 TT 20 0.05 19 0.042 MEGA-1 1149 0.7 TC 463 0.344 528 0.3TT 62 0.05 77 0.044 hCV31199195 KCTD10 rs10850234 A C A MEGA-2 1905 0.7CA 321 0.257 778 0.28 CC 33 0.03 81 0.029 C LETS 328 0.7 CA 142 0.321111 0.25 CC 12 0.03 14 0.031 MEGA-1 1214 0.7 CA 423 0.305 486 0.28 CC 520.04 52 0.03 hCV11975651 SERPINC1 rs677 C G C LETS 363 0.8 GC 96 0.21877 0.17 GG 3 0.01 11 0.024 C MEGA-2 2115 0.8 GC 252 0.201 620 0.22 GG 130.01 42 0.015 G LETS 363 0.8 GC 96 0.218 77 0.17 GG 3 0.01 11 0.024

TABLE 25 Table 25. Age- and sex-adjusted association of 52 SNPs withisolated PE in MEGA (p <= 0.05) Gene Ref- NonRef- Risk Control CaseCase- Control- Marker Symbol RS number Allele Allele Allele RAF ModelParameter P-value OddsRatio OR95l OR95u Genot Count3 Freq3 Count3hCV11503414 FGG rs2066865 G A A 0.265941 general hCV11503414.AA  7.9E−071.7644 1.40836 2.21043 GG 548 0.4656 2426 recessive hCV11503414.AA.rec2.65E−05 1.5897 1.28058 1.97356 GG 548 0.4656 2426 dominanthCV11503414.GG.dom 9.06E−06 1.3387 1.17692 1.5228 GG 548 0.4656 2426addiitive hCV11503414.AA.AG.adtv 1.38E−07 1.3027 1.18064 1.43736 GG 5480.4656 2426 general hCV111503414.AG 0.000825 1.2612 1.1008 1.44487 GG548 0.4656 2426 hCV11503469 FGG rs2066854 T A A 0.266985 generalhCV11503469.AA 2.7E−06 1.7154 1.36923 2.14908 TT 551 0.4677 2423recessive hCV11503469.AA.rec 6.76E−05 1.5525 1.25045 1.92746 TT 5510.4677 2423 dominant hCV11503469.TT.dom 2.15E−05 1.3219 1.16224 1.50354TT 551 0.4677 2423 additive hCV11503469.AA.AT.adtv   5E−07 1.28671.16622 1.41954 TT 551 0.4677 2423 general hCV11503469.AT 0.0013321.2492 1.09047 1.43109 TT 551 0.4677 2423 hCV11503470 rs1800788 C T T0.208112 general hCV11503470.TC 0.003347 1.2266 1.07016 1.40596 CC 6930.5868 2864 dominant hCV11503470.CC.dom 0.003532 1.2149 1.06597 1.38472CC 693 0.5868 2864 additive hCV11503470.TT.TC.adtv 0.010682 1.14921.03283 1.2787 CC 693 0.5868 2864 hCV11786258 KLKB1 rs4253303 G A A0.393142 general hCV11786258.AA 0.041072 1.2175 1.00801 1.47061 GG 4100.348 1662 recessive hCV11786258.AA.rec 0.048475 1.1868 1.00115 1.40687GG 410 0.348 1662 hCV11975250 F5 rs6025 C T T 0.026408 dominanthCV11975250.CC.dom 9.91E−08 1.9003 1.50059 2.4065 CC 1084 0.9071 4311general hCV11975250.TC 2.06E−07 1.8887 1.48577 2.40092 CC 1084 0.90714311 additive hCV11975250.TT.TC.adtv 1.25E−07 1.8329 1.46414 2.29465 CC1084 0.9071 4311 hCV1202883 MTHFR rs1801133 G A G 0.69837 generalhCV1202883.AA 0.025299 0.7168 0.53542 0.95963 GG 582 0.4818 2132recessive hCV1202883.AA.rec 0.031062 0.7312 0.55017 0.97191 GG 5820.4818 2132 hCV12066124 F11 rs2036914 C T C 0.518478 generalhCV12066124.TT 0.00048 0.7255 0.6059 0.8687 CC 389 0.3316 1226 dominanthCV12066124.CC.dom 4.11E−05 0.7487 0.65205 0.85979 CC 389 0.3316 1226general hCV12066124.TC 0.000273 0.7598 0.65525 0.88093 CC 389 0.33161226 additive hCV12066124.TT.TC.adtv 0.000208 0.8423 0.76928 0.92226 CC389 0.3316 1226 hCV12092542 CASP5 rs507879 T C T 0.548201 recessivehCV12092542.CC.rec 0.006664 0.7876 0.66284 0.93587 TT 353 0.3046 1170general hCV12092542.CC 0.03597 0.8101 0.66544 0.98631 TT 353 0.3046 1170hCV15860433 rs2070006 C T T 0.395787 general hCV15860433.TT 0.0017491.3524 1.11945 1.63385 CC 369 0.314 1665 dominant hCV15860433.CC.dom0.0005 1.2764 1.11253 1.46444 CC 369 0.314 1665 general hCV15860433.TC0.002575 1.2504 1.08131 1.44596 CC 369 0.314 1665 recessivehCV15860433.TT.rec 0.045925 1.1859 1.00309 1.40199 CC 369 0.314 1665additive hCV15860433.TT.TC.adtv 0.000548 1.1753 1.07241 1.28797 CC 3690.314 1665 hCV15949414 XYLB rs2234628 G A G 0.947951 generalhCV15949414.AG 0.01515 0.744 0.58608 0.94452 GG 1087 0.9204 4059dominant hCV15949414.GG.dom 0.027067 0.7696 0.6102 0.97075 GG 10870.9204 4059 hCV15968043 CYP4V2 rs2292423 T A A 0.409182 generalhCV15968043.AA 0.036009 1.2214 1.01314 1.47241 TT 383 0.329 1562recessive hCV15968043.AA.rec 0.040079 1.1899 1.0079 1.40466 TT 383 0.3291562 hCV16180170 SERPINC1 rs2227589 C T T 0.09279 general hCV16180170.TT0.024575 1.8494 1.08198 3.16127 CC 941 0.7842 3782 recessivehCV16180170.TT.rec 0.035841 1.7737 1.03862 3.02895 CC 941 0.7842 3782dominant hCV16180170.CC.dom 0.001751 1.2856 1.09842 1.5046 CC 941 0.78423782 additive hCV16180170.TT.TC.adtv 0.000708 1.2794 1.10936 1.47544 CC941 0.7842 3782 general hCV16180170.TC 0.006258 1.2536 1.06609 1.4742 CC941 0.7842 3782 hCV1842260 LOC642043 rs2281390 G T T 0.171422 generalhCV1842260.TG 0.02393 1.1745 1.02147 1.35049 GG 796 0.6589 3177 dominanthCV1842260.GG.dom 0.03773 1.1535 1.00813 1.31976 GG 796 0.6589 3177hCV1859855 GOLGA3/POLE rs2291260 T C C 0.218551 recessivehCV1859855.CC.rec 0.000395 1.6269 1.24298 2.12951 TT 742 0.622 2757general hCV1859855.CC 0.001859 1.5434 1.17426 2.02848 TT 742 0.622 2757T 0.781449 general hCV1859855.CT 0.034049 0.8603 0.74856 0.98874 TT 7420.622 2757 hCV2103346 DKFZP564J102 rs11733307 T C C 0.441711 additivehCV2103346.CC.CT.adtv 0.043311 1.0967 1.00278 1.19951 TT 343 0.2917 1450hCV22272267 KLKB1 rs3733402 A G A 0.513535 general hCV22272267.GA3.14E−05 0.7277 0.62658 0.84518 AA 378 0.3206 1178 dominanthCV22272267.AA.dom 4.55E−05 0.7483 0.65098 0.86023 AA 378 0.3206 1178general hCV22272267.GG 0.010202 0.7927 0.66394 0.94642 AA 378 0.32061178 additive hCV22272267.GG.GA.adtv 0.004727 0.8775 0.80143 0.96077 AA378 0.3206 1178 hCV233148 AKT3/SDCCAG8 rs1417121 G C C 0.27821 generalhCV233148.CC 0.027568 1.2973 1.02917 1.6352 GG 585 0.497 2340 recessivehCV233148.CC.rec 0.036974 1.2684 1.01448 1.58595 GG 585 0.497 2340hCV25474413 F11 rs3822057 A C C 0.483878 general hCV25474413.CC 0.0001651.4124 1.18018 1.6902 AA 273 0.2312 1218 recessive hCV25474413.CC.rec0.000395 1.2968 1.12318 1.49737 AA 273 0.2312 1218 dominanthCV25474413.AA.dom 0.007883 1.2264 1.055 1.42566 AA 273 0.2312 1218additive hCV25474413.CC.CA.adtv 0.000155 1.1902 1.08754 1.30266 AA 2730.2312 1218 hCV25615302 CUEDC1 rs17762338 C T T 0.178556 generalhCV25615302.TC 0.01558 1.1856 1.03281 1.36102 CC 774 0.645 3107 dominanthCV25615302.CC.dom 0.032234 1.1572 1.01246 1.32268 CC 774 0.645 3107hCV25620145 PROCR rs867186 A G G 0.124401 additivehCV25620145.GG.GA.adtv 0.013407 1.179 1.03473 1.34333 AA 884 0.7354 3514dominant hCV25620145.AA.dom 0.026984 1.1783 1.01886 1.36277 AA 8840.7354 3514 hCV25748719 NAP5 NONE C T C 0.7673 general hCV25748719.TT0.033944 0.705 0.51043 0.97385 CC 738 0.6165 2693 additivehCV25748719.TT.TC.adtv 0.021016 0.8782 0.78644 0.98061 CC 738 0.61652693 hCV25768636 CCDC36/USP19 rs4279134 G A G 0.648673 recessivehCV25768636.AA.rec 0.032703 0.7973 0.64757 0.98153 GG 502 0.4265 1910hCV2590858 ACDCY9 rs2230738 C T C 0.733461 general hCV2590858.TT0.022606 0.7254 0.55052 0.95594 CC 654 0.5566 2418 recessivehCV2590858.TT.rec 0.020267 0.726 0.55407 0.95138 CC 654 0.5566 2418hCV25990131 CYP4V2 rs13146272 A C A 0.64085 general hCV25990131.CC0.009124 0.7483 0.60174 0.93053 AA 515 0.4522 1814 recessivehCV25990131.CC.rec 0.029035 0.7944 0.64605 0.97675 AA 515 0.4522 1814dominant hCV25990131.AA.dom 0.021499 0.8571 0.7516 0.97752 AA 515 0.45221814 additive hCV25990131.CC.CA.adtv 0.006142 0.8728 0.79182 0.962 AA515 0.4522 1814 hCV26175114 TUBA4A rs3731892 A G G 0.108496 recessivehCV26175114.GG.rec 0.010391 1.6966 1.13236 2.54198 AA 936 0.7939 3655general hCV26175114.GG 0.011269 1.6893 1.12616 2.53402 AA 936 0.79393655 hCV27474895 F11 rs3756011 C A A 0.405226 general hCV27474895.AA 1.4E−05 1.5002 1.24929 1.80148 CC 357 0.3036 1619 recessivehCV27474895.AA.rec 0.000287 1.344 1.14551 1.57678 CC 357 0.3036 1619dominant hCV27474895.CC.dom 0.000437 1.2822 1.11632 1.47271 CC 3570.3036 1619 additive hCV27474895.AA.AC.adtv 1.39E−05 1.2226 1.116661.33868 CC 357 0.3036 1619 general hCV27474895.AC 0.013465 1.20441.03922 1.3958 CC 357 0.3036 1619 hCV27474984 PIK3R1 rs3756668 G A A0.448895 general hCV27474984.AA 0.003924 1.3009 1.08794 1.55547 GG 3290.2769 1416 recessive hCV27474984.AA.rec 0.013232 1.2106 1.04073 1.40818GG 329 0.2769 1416 dominant hCV27474984.GG.dom 0.024908 1.1763 1.020691.35558 GG 329 0.2769 1416 additive hCV27474984.AA.AG.adtv 0.0041311.1397 1.04227 1.24624 GG 329 0.2769 1416 hCV27477533 F11 rs3756008 A TT 0.395815 general hCV27477533.TT 5.37E−05 1.4656 1.21747 1.76441 AA 3690.3132 1671 recessive hCV27477533.TT.rec 0.00183 1.2972 1.10137 1.52774AA 369 0.3132 1671 dominant hCV27477533.AA.dom 0.000252 1.2923 1.126491.48254 AA 369 0.3132 1671 general hCV27477533.TA 0.004944 1.23261.06535 1.42618 AA 369 0.3132 1671 additive hCV27477533.TT.TA.adtv3.06E−05 1.2135 1.10796 1.32902 AA 369 0.3132 1671 hCV27902808 CYP4V2rs4253236 C T C 0.636333 general hCV27902808.TT 0.037699 0.8022 0.651570.98755 CC 529 0.4494 1838 dominant hCV27902808.CC.dom 0.007416 0.8380.73623 0.95372 CC 529 0.4494 1838 general hCV27902808.TC 0.01876 0.84840.73967 0.97306 CC 529 0.4494 1838 additive hCV27902808.TT.TC.adtv0.009101 0.8808 0.80074 0.96896 CC 529 0.4494 1838 hCV2892877 FGA rs6050T C C 0.23658 dominant hCV2892877.TT.dom 2.84E−05 1.3303 1.16388 1.52044TT 503 0.4594 2237 general hCV2892877.CT 3.74E−05 1.3257 1.15939 1.51579TT 503 0.4594 2237 additive hCV2892877.CC.CT.adtv 2.16E−05 1.32651.16435 1.51125 TT 503 0.4594 2237 hCV2915511 OBSL1/STK11IP rs627530 T CC 0.036056 general hCV2915511.CC 0.018869 2.8308 1.18768 6.74695 TT 11030.9154 4284 recessive hCV2915511.CC.rec 0.020235 2.7975 1.17396 6.66633TT 1103 0.9154 4284 additive hCV2915511.CC.CT.adtv 0.027831 1.27061.02644 1.57275 TT 1103 0.9154 4284 hCV29821005 LOC728284 rs6552970 C TC 0.829809 general hCV29821005.TC 0.013769 0.8228 0.70448 0.96093 CC 8270.7267 3068 hCV30562347 F11 rs4253418 G A G 0.956444 generalhCV30562347.AG 0.04875 0.7731 0.59856 0.99859 GG 1098 0.9313 4119hCV3180954 PTCRA rs9471966 G A G 0.734992 general hCV3180954.AA 0.0432890.7611 0.58411 0.9918 GG 685 0.5689 2507 hCV32291301 KLKB1 rs4253302 A GA 0.837091 general hCV32291301.GA 5.63E−05 0.727 0.62248 0.84899 AA 8930.7568 3177 dominant hCV32291301.AA.dom 0.000204 0.756 0.65222 0.87625AA 893 0.7568 3177 additive hCV32291301.GG.GA.adtv 0.00251 0.82040.72152 0.93278 AA 893 0.7568 3177 hCV3230038 F11 rs2289252 C T T0.403825 general hCV3230038.TT 5.16E−06 1.5316 1.27506 1.83965 CC 3550.3014 1626 recessive hCV3230038.TT.rec 0.000163 1.3601 1.15911 1.59587CC 355 0.3014 1626 dominant hCV3230038.CC.dom 0.000187 1.3025 1.133891.49618 CC 355 0.3014 1626 additive hCV3230038.TT.TC.adtv  4.8E−061.2359 1.12865 1.3533 CC 355 0.3014 1626 general hCV3230038.TC 0.0077541.2218 1.05429 1.41601 CC 355 0.3014 1626 hCV3230096 CYP4V2 rs3817184 CT T 0.415431 general hCV3230096.TT 0.021851 1.2411 1.03187 1.49283 CC374 0.3175 1546 recessive hCV3230096.TT.rec 0.036521 1.1894 1.010931.39932 CC 374 0.3175 1546 additive hCV3230096.TT.TC.adtv 0.026457 1.1091.01216 1.215 CC 374 0.3175 1546 hCV3230113 CYP4V2 rs1053094 A T T0.490487 recessive hCV3230113.TT.rec 0.007751 1.2185 1.05354 1.40928 AA286 0.2436 1158 general hCV3230113.TT 0.030129 1.22 1.0193 1.46022 AA286 0.2436 1158 additive hCV3230113.TT.TA.adtv 0.029142 1.1067 1.010351.21226 AA 286 0.2436 1158 hCV3272537 TIAM1 rs497689 T A A 0.442161general hCV3272537.AT 0.003248 1.2507 1.07759 1.45156 TT 330 0.2782 1449dominant hCV3272537.TT.dom 0.012334 1.1982 1.03998 1.38055 TT 330 0.27821449 hCV540410 LASP1 rs609529 T A A 0.063164 general hCV540410.AA0.007939 2.6467 1.29008 5.42985 TT 1037 0.8649 3967 recessivehCV540410.AA.rec 0.008389 2.6271 1.28109 5.38731 TT 1037 0.8649 3967hCV596331 F9 rs6048 A G A 0.698278 general hCV596331.GG 0.005303 0.77410.64659 0.92677 AA 759 0.6309 2719 recessive hCV596331.GG.rec 0.0113470.7941 0.66432 0.94926 AA 759 0.6309 2719 dominant hCV596331.AA.dom0.001786 0.8083 0.70723 0.92377 AA 759 0.6309 2719 additivehCV596331.GG.GA.adtv 0.001633 0.8731 0.80244 0.95003 AA 759 0.6309 2719hCV7422466 C9orf103 rs1052690 A C A 0.803646 general hCV7422466.CA0.001726 0.7929 0.68582 0.91676 AA 815 0.6901 2630 dominanthCV7422466.AA.dom 0.002711 0.8083 0.70328 0.92892 AA 815 0.6901 2630additive hCV7422466.CC.CA.adtv 0.011048 0.8557 0.75881 0.96499 AA 8150.6901 2630 hCV7581501 USP45 rs1323717 G C G 0.879567 generalhCV7581501.CG 0.043619 0.8471 0.72094 0.99526 GG 956 0.796 3528hCV7625318 PLEKHG4 rs3868142 G A A 0.084256 general hCV7625318.AA0.002718 2.0943 1.29169 3.39574 GG 992 0.8267 3877 recessivehCV7625318.AA.rec 0.002865 2.0835 1.28604 3.37549 GG 992 0.8267 3877hCV8241630 F11 rs925451 G A A 0.379287 general hCV8241630.AA 3.67E−051.4822 1.22955 1.78668 GG 394 0.3333 1768 recessive hCV8241630.AA.rec0.001099 1.3212 1.11769 1.56172 GG 394 0.3333 1768 dominanthCV8241630.GG.dom 0.00023 1.2889 1.12609 1.4753 GG 394 0.3333 1768general hCV8241630.AG 0.005449 1.2259 1.06187 1.41517 GG 394 0.3333 1768additive hCV8241630.AA.AG.adtv 2.03E−05 1.2188 1.11277 1.33486 GG 3940.3333 1768 hCV8361354 PANX1 rs1138800 C A A 0.374456 recessivehCV8361354.AA.rec 0.011342 1.254 1.05247 1.49423 CC 464 0.3863 1774general hCV8361354.AA 0.046424 1.2139 1.00308 1.46897 CC 464 0.3863 1774hCV8717873 GP6/RDH13 rs1613662 A G A 0.816402 dominant hCV8717873.AA.dom0.00637 0.8245 0.71782 0.94713 AA 849 0.7063 3059 general hCV8717873.GA0.011484 0.8311 0.72009 0.95931 AA 849 0.7063 3059 additivehCV8717873.GG.GA.adtv 0.006619 0.845 0.74824 0.95422 AA 849 0.7063 3059hCV8726802 F2 rs1799963 G A A 0.009998 additive hCV8726802.AA.AG.adtv0.001832 1.7876 1.24051 2.57599 GG 1154 0.9649 4509 dominanthCV8726802.GG.dom 0.002881 1.7586 1.21319 2.54921 GG 1154 0.9649 4509general hCV8726802.AG 0.004755 1.7145 1.17921 2.49277 GG 1154 0.96494509 hCV8911768 SERPINC1 rs941988 C T T 0.095461 additivehCV8911768.TT.TC.adtv 0.045997 1.2308 1.0037 1.50923 CC 432 0.7869 2274hCV8919444 F5 rs4524 T C T 0.737678 general hCV8919444.CC 0.00142 0.62170.46423 0.83249 TT 703 0.5993 2466 recessive hCV8919444.CC.rec 0.0051260.6634 0.49765 0.88423 TT 703 0.5993 2466 dominant hCV8919444.TT.dom0.001654 0.8105 0.71104 0.92383 TT 703 0.5993 2466 additivehCV8919444.CC.CT.adtv 0.000259 0.8188 0.73558 0.91152 TT 703 0.5993 2466general hCV8919444.CT 0.016842 0.8466 0.73854 0.97047 TT 703 0.5993 2466hCV9102827 GPATCH4 rs3795733 T C C 0.258025 general hCV9102827.CC0.038395 1.2746 1.01305 1.6037 TT 614 0.5217 2331 dominanthCV9102827.TT.dom 0.0061 1.1997 1.05332 1.36641 TT 614 0.5217 2331general hCV9102827.CT 0.018086 1.1819 1.02896 1.35755 TT 614 0.5217 2331additive hCV9102827.CC.CT.adtv 0.005678 1.1485 1.04116 1.26683 TT 6140.5217 2331 hDV70683382 RABGAP1L rs16846815 G C C 0.061982 generalhDV70683382.CC 0.040966 3.2342 1.04937 9.96795 GG 468 0.854 2439recessive hDV70683382.CC.rec 0.044861 3.1627 1.02675 9.74207 GG 4680.854 2439 Gene Ref- NonRef- Risk Control Control- Case Case- Control-Control- Case- Case- Control- Control- Marker Symbol RS number AlleleAllele Allele RAF Model Freq3 Genot2 Count4 Freq4 Count4 Freq4 Genot3Count5 Freq5 Count5 Freq5 hCV11503414 FGG rs2066865 G A A 0.265941general 0.539 AG 501 0.426 1756 0.3901 AA 128 0.1088 319 0.071 recessive0.539 AG 501 0.426 1756 0.3901 AA 128 0.1088 319 0.071 dominant 0.539 AG501 0.426 1756 0.3901 AA 128 0.1088 319 0.071 addiitive 0.539 AG 5010.426 1756 0.3901 AA 128 0.1088 319 0.071 general 0.539 AG 501 0.4261756 0.3901 AA 128 0.1088 319 0.071 hCV11503469 FGG rs2066854 T A A0.266985 general 0.538 AT 500 0.424 1757 0.3901 AA 127 0.1078 324 0.072recessive 0.538 AT 500 0.424 1757 0.3901 AA 127 0.1078 324 0.072dominant 0.538 AT 500 0.424 1757 0.3901 AA 127 0.1078 324 0.072 additive0.538 AT 500 0.424 1757 0.3901 AA 127 0.1078 324 0.072 general 0.538 AT500 0.424 1757 0.3901 AA 127 0.1078 324 0.072 hCV11503470 rs1800788 C TT 0.208112 general 0.6331 TC 426 0.361 1437 0.3176 TT 62 0.0525 2230.049 dominant 0.6331 TC 426 0.361 1437 0.3176 TT 62 0.0525 223 0.049additive 0.6331 TC 426 0.361 1437 0.3176 TT 62 0.0525 223 0.049hCV11786258 KLKB1 rs4253303 G A A 0.393142 general 0.3677 AG 559 0.4752162 0.4783 AA 209 0.1774 696 0.154 recessive 0.3677 AG 559 0.475 21620.4783 AA 209 0.1774 696 0.154 hCV11975250 F5 rs6025 C T T 0.026408dominant 0.9487 TC 107 0.09 226 0.0497 TT 4 0.0033 7 0.002 general0.9487 TC 107 0.09 226 0.0497 TT 4 0.0033 7 0.002 additive 0.9487 TC 1070.09 226 0.0497 TT 4 0.0033 7 0.002 hCV1202883 MTHFR rs1801133 G A G0.69837 general 0.4635 AG 566 0.469 2161 0.4698 AA 60 0.0497 307 0.067recessive 0.4635 AG 566 0.469 2161 0.4698 AA 60 0.0497 307 0.067hCV12066124 F11 rs2036914 C T C 0.518478 general 0.2713 TC 540 0.46 22340.4944 TT 244 0.208 1059 0.234 dominant 0.2713 TC 540 0.46 2234 0.4944TT 244 0.208 1059 0.234 general 0.2713 TC 540 0.46 2234 0.4944 TT 2440.208 1059 0.234 additive 0.2713 TC 540 0.46 2234 0.4944 TT 244 0.2081059 0.234 hCV12092542 CASP5 rs507879 T C T 0.548201 recessive 0.3008 CT610 0.526 1925 0.4949 CC 196 0.1691 795 0.204 general 0.3008 CT 6100.526 1925 0.4949 CC 196 0.1691 795 0.204 hCV15860433 rs2070006 C T T0.395787 general 0.3692 TC 588 0.5 2120 0.4701 TT 218 0.1855 725 0.161dominant 0.3692 TC 588 0.5 2120 0.4701 TT 218 0.1855 725 0.161 general0.3692 TC 588 0.5 2120 0.4701 TT 218 0.1855 725 0.161 recessive 0.3692TC 588 0.5 2120 0.4701 TT 218 0.1855 725 0.161 additive 0.3692 TC 5880.5 2120 0.4701 TT 218 0.1855 725 0.161 hCV15949414 XYLB rs2234628 G A G0.947951 general 0.899 AG 88 0.075 442 0.0979 AA 6 0.0051 14 0.003dominant 0.899 AG 88 0.075 442 0.0979 AA 6 0.0051 14 0.003 hCV15968043CYP4V2 rs2292423 T A A 0.409182 general 0.3481 AT 558 0.479 2178 0.4854AA 223 0.1916 747 0.166 recessive 0.3481 AT 558 0.479 2178 0.4854 AA 2230.1916 747 0.166 hCV16180170 SERPINC1 rs2227589 C T T 0.09279 general0.8238 TC 239 0.199 766 0.1668 TT 20 0.0167 43 0.009 recessive 0.8238 TC239 0.199 766 0.1668 TT 20 0.0167 43 0.009 dominant 0.8238 TC 239 0.199766 0.1668 TT 20 0.0167 43 0.009 additive 0.8238 TC 239 0.199 766 0.1668TT 20 0.0167 43 0.009 general 0.8238 TC 239 0.199 766 0.1668 TT 200.0167 43 0.009 hCV1842260 LOC642043 rs2281390 G T T 0.171422 general0.692 TG 372 0.308 1254 0.2731 TT 40 0.0331 160 0.035 dominant 0.692 TG372 0.308 1254 0.2731 TT 40 0.0331 160 0.035 hCV1859855 GOLGA3/POLErs2291260 T C C 0.218551 recessive 0.6053 CT 371 0.311 1605 0.3524 CC 800.0671 193 0.042 general 0.6053 CT 371 0.311 1605 0.3524 CC 80 0.0671193 0.042 T 0.781449 general 0.6053 CT 371 0.311 1605 0.3524 CC 800.0671 193 0.042 hCV2103346 DKFZP564J102 rs11733307 T C C 0.441711additive 0.3214 CT 571 0.486 2138 0.4738 CC 262 0.2228 924 0.205hCV22272267 KLKB1 rs3733402 A G A 0.513535 general 0.2614 GA 532 0.4512273 0.5043 GG 269 0.2282 1056 0.234 dominant 0.2614 GA 532 0.451 22730.5043 GG 269 0.2282 1056 0.234 general 0.2614 GA 532 0.451 2273 0.5043GG 269 0.2282 1056 0.234 additive 0.2614 GA 532 0.451 2273 0.5043 GG 2690.2282 1056 0.234 hCV233148 AKT3/SDCCAG8 rs1417121 G C C 0.27821 general0.5198 CG 479 0.407 1819 0.404 CC 113 0.096 343 0.076 recessive 0.5198CG 479 0.407 1819 0.404 CC 113 0.096 343 0.076 hCV25474413 F11 rs3822057A C C 0.483878 general 0.269 CA 570 0.483 2238 0.4943 CC 338 0.2862 10720.237 recessive 0.269 CA 570 0.483 2238 0.4943 CC 338 0.2862 1072 0.237dominant 0.269 CA 570 0.483 2238 0.4943 CC 338 0.2862 1072 0.237additive 0.269 CA 570 0.483 2238 0.4943 CC 338 0.2862 1072 0.237hCV25615302 CUEDC1 rs17762338 C T T 0.178556 general 0.6778 TC 389 0.3241317 0.2873 TT 37 0.0308 160 0.035 dominant 0.6778 TC 389 0.324 13170.2873 TT 37 0.0308 160 0.035 hCV25620145 PROCR rs867186 A G G 0.124401additive 0.7656 GA 292 0.243 1010 0.22 GG 26 0.0216 66 0.014 dominant0.7656 GA 292 0.243 1010 0.22 GG 26 0.0216 66 0.014 hCV25748719 NAP5NONE C T C 0.7673 general 0.5879 TC 412 0.344 1644 0.3589 TT 47 0.0393244 0.053 additive 0.5879 TC 412 0.344 1644 0.3589 TT 47 0.0393 2440.053 hCV25768636 CCDC36/USP19 rs4279134 G A G 0.648673 recessive 0.4226AG 554 0.471 2044 0.4522 AA 121 0.1028 566 0.125 hCV2590858 ACDCY9rs2230738 C T C 0.733461 general 0.5441 TC 454 0.386 1683 0.3787 TT 670.057 343 0.077 recessive 0.5441 TC 454 0.386 1683 0.3787 TT 67 0.057343 0.077 hCV25990131 CYP4V2 rs13146272 A C A 0.64085 general 0.4144 CA501 0.44 1982 0.4528 CC 123 0.108 581 0.133 recessive 0.4144 CA 501 0.441982 0.4528 CC 123 0.108 581 0.133 dominant 0.4144 CA 501 0.44 19820.4528 CC 123 0.108 581 0.133 additive 0.4144 CA 501 0.44 1982 0.4528 CC123 0.108 581 0.133 hCV26175114 TUBA4A rs3731892 A G G 0.108496recessive 0.8003 GA 208 0.176 833 0.1824 GG 35 0.0297 79 0.017 general0.8003 GA 208 0.176 833 0.1824 GG 35 0.0297 79 0.017 hCV27474895 F11rs3756011 C A A 0.405226 general 0.3585 AC 567 0.482 2134 0.4725 AA 2520.2143 763 0.169 recessive 0.3585 AC 567 0.482 2134 0.4725 AA 252 0.2143763 0.169 dominant 0.3585 AC 567 0.482 2134 0.4725 AA 252 0.2143 7630.169 additive 0.3585 AC 567 0.482 2134 0.4725 AA 252 0.2143 763 0.169general 0.3585 AC 567 0.482 2134 0.4725 AA 252 0.2143 763 0.169hCV27474984 PIK3R1 rs3756668 G A A 0.448895 general 0.3099 AG 573 0.4822204 0.4824 AA 286 0.2407 949 0.208 recessive 0.3099 AG 573 0.482 22040.4824 AA 286 0.2407 949 0.208 dominant 0.3099 AG 573 0.482 2204 0.4824AA 286 0.2407 949 0.208 additive 0.3099 AG 573 0.482 2204 0.4824 AA 2860.2407 949 0.208 hCV27477533 F11 rs3756008 A T T 0.395815 general 0.37TA 574 0.487 2115 0.4683 TT 235 0.1995 730 0.162 recessive 0.37 TA 5740.487 2115 0.4683 TT 235 0.1995 730 0.162 dominant 0.37 TA 574 0.4872115 0.4683 TT 235 0.1995 730 0.162 general 0.37 TA 574 0.487 21150.4683 TT 235 0.1995 730 0.162 additive 0.37 TA 574 0.487 2115 0.4683 TT235 0.1995 730 0.162 hCV27902808 CYP4V2 rs4253236 C T C 0.636333 general0.4065 TC 508 0.432 2079 0.4598 TT 140 0.1189 605 0.134 dominant 0.4065TC 508 0.432 2079 0.4598 TT 140 0.1189 605 0.134 general 0.4065 TC 5080.432 2079 0.4598 TT 140 0.1189 605 0.134 additive 0.4065 TC 508 0.4322079 0.4598 TT 140 0.1189 605 0.134 hCV2892877 FGA rs6050 T C C 0.23658dominant 0.5314 CT 584 0.533 1954 0.4641 CC 8 0.0073 19 0.005 general0.5314 CT 584 0.533 1954 0.4641 CC 8 0.0073 19 0.005 additive 0.5314 CT584 0.533 1954 0.4641 CC 8 0.0073 19 0.005 hCV2915511 OBSL1/STK11IPrs627530 T C C 0.036056 general 0.9305 CT 93 0.077 308 0.0669 CC 90.0075 12 0.003 recessive 0.9305 CT 93 0.077 308 0.0669 CC 9 0.0075 120.003 additive 0.9305 CT 93 0.077 308 0.0669 CC 9 0.0075 12 0.003hCV29821005 LOC728284 rs6552970 C T C 0.829809 general 0.6976 TC 2590.228 1163 0.2644 TT 52 0.0457 167 0.038 hCV30562347 F11 rs4253418 G A G0.956444 general 0.9153 AG 76 0.064 370 0.0822 AA 5 0.0042 11 0.002hCV3180954 PTCRA rs9471966 G A G 0.734992 general 0.5473 AG 445 0.371720 0.3755 AA 74 0.0615 354 0.077 hCV32291301 KLKB1 rs4253302 A G A0.837091 general 0.7023 GA 250 0.212 1220 0.2697 GG 37 0.0314 127 0.028dominant 0.7023 GA 250 0.212 1220 0.2697 GG 37 0.0314 127 0.028 additive0.7023 GA 250 0.212 1220 0.2697 GG 37 0.0314 127 0.028 hCV3230038 F11rs2289252 C T T 0.403825 general 0.3595 TC 571 0.485 2141 0.4734 TT 2520.2139 756 0.167 recessive 0.3595 TC 571 0.485 2141 0.4734 TT 252 0.2139756 0.167 dominant 0.3595 TC 571 0.485 2141 0.4734 TT 252 0.2139 7560.167 additive 0.3595 TC 571 0.485 2141 0.4734 TT 252 0.2139 756 0.167general 0.3595 TC 571 0.485 2141 0.4734 TT 252 0.2139 756 0.167hCV3230096 CYP4V2 rs3817184 C T T 0.415431 general 0.3423 TC 569 0.4832189 0.4846 TT 235 0.1995 782 0.173 recessive 0.3423 TC 569 0.483 21890.4846 TT 235 0.1995 782 0.173 additive 0.3423 TC 569 0.483 2189 0.4846TT 235 0.1995 782 0.173 hCV3230113 CYP4V2 rs1053094 A T T 0.490487recessive 0.2562 TA 565 0.481 2290 0.5066 TT 323 0.2751 1072 0.237general 0.2562 TA 565 0.481 2290 0.5066 TT 323 0.2751 1072 0.237additive 0.2562 TA 565 0.481 2290 0.5066 TT 323 0.2751 1072 0.237hCV3272537 TIAM1 rs497689 T A A 0.442161 general 0.3169 AT 630 0.5312204 0.482 AA 226 0.1906 920 0.201 dominant 0.3169 AT 630 0.531 22040.482 AA 226 0.1906 920 0.201 hCV540410 LASP1 rs609529 T A A 0.063164general 0.8777 AT 149 0.124 535 0.1184 AA 13 0.0108 18 0.004 recessive0.8777 AT 149 0.124 535 0.1184 AA 13 0.0108 18 0.004 hCV596331 F9 rs6048A G A 0.698278 general 0.5928 GA 259 0.215 968 0.211 GG 185 0.1538 9000.196 recessive 0.5928 GA 259 0.215 968 0.211 GG 185 0.1538 900 0.196dominant 0.5928 GA 259 0.215 968 0.211 GG 185 0.1538 900 0.196 additive0.5928 GA 259 0.215 968 0.211 GG 185 0.1538 900 0.196 hCV7422466C9orf103 rs1052690 A C A 0.803646 general 0.6435 CA 323 0.273 13090.3203 CC 43 0.0364 148 0.036 dominant 0.6435 CA 323 0.273 1309 0.3203CC 43 0.0364 148 0.036 additive 0.6435 CA 323 0.273 1309 0.3203 CC 430.0364 148 0.036 hCV7581501 USP45 rs1323717 G C G 0.879567 general0.7718 CG 227 0.189 985 0.2155 CC 18 0.015 58 0.013 hCV7625318 PLEKHG4rs3868142 G A A 0.084256 general 0.8419 AG 182 0.152 680 0.1477 AA 260.0217 48 0.01 recessive 0.8419 AG 182 0.152 680 0.1477 AA 26 0.0217 480.01 hCV8241630 F11 rs925451 G A A 0.379287 general 0.3912 AG 565 0.4782074 0.459 AA 223 0.1887 677 0.15 recessive 0.3912 AG 565 0.478 20740.459 AA 223 0.1887 677 0.15 dominant 0.3912 AG 565 0.478 2074 0.459 AA223 0.1887 677 0.15 general 0.3912 AG 565 0.478 2074 0.459 AA 223 0.1887677 0.15 additive 0.3912 AG 565 0.478 2074 0.459 AA 223 0.1887 677 0.15hCV8361354 PANX1 rs1138800 C A A 0.374456 recessive 0.3863 AC 541 0.452197 0.4784 AA 196 0.1632 621 0.135 general 0.3863 AC 541 0.45 21970.4784 AA 196 0.1632 621 0.135 hCV8717873 GP6/RDH13 rs1613662 A G A0.816402 dominant 0.6654 GA 321 0.267 1388 0.3019 GG 32 0.0266 150 0.033general 0.6654 GA 321 0.267 1388 0.3019 GG 32 0.0266 150 0.033 additive0.6654 GA 321 0.267 1388 0.3019 GG 32 0.0266 150 0.033 hCV8726802 F2rs1799963 G A A 0.009998 additive 0.98 AG 41 0.034 92 0.02 AA 1 0.0008 00 dominant 0.98 AG 41 0.034 92 0.02 AA 1 0.0008 0 0 general 0.98 AG 410.034 92 0.02 AA 1 0.0008 0 0 hCV8911768 SERPINC1 rs941988 C T T0.095461 additive 0.8192 TC 107 0.195 474 0.1707 TT 10 0.0182 28 0.01hCV8919444 F5 rs4524 T C T 0.737678 general 0.5475 CT 412 0.351 17130.3803 CC 58 0.0494 325 0.072 recessive 0.5475 CT 412 0.351 1713 0.3803CC 58 0.0494 325 0.072 dominant 0.5475 CT 412 0.351 1713 0.3803 CC 580.0494 325 0.072 additive 0.5475 CT 412 0.351 1713 0.3803 CC 58 0.0494325 0.072 general 0.5475 CT 412 0.351 1713 0.3803 CC 58 0.0494 325 0.072hCV9102827 GPATCH4 rs3795733 T C C 0.258025 general 0.5669 CT 448 0.3811440 0.3502 CC 115 0.0977 341 0.083 dominant 0.5669 CT 448 0.381 14400.3502 CC 115 0.0977 341 0.083 general 0.5669 CT 448 0.381 1440 0.3502CC 115 0.0977 341 0.083 additive 0.5669 CT 448 0.381 1440 0.3502 CC 1150.0977 341 0.083 hDV70683382 RABGAP1L rs16846815 G C C 0.061982 general0.8789 CG 75 0.137 328 0.1182 CC 5 0.0091 8 0.003 recessive 0.8789 CG 750.137 328 0.1182 CC 5 0.0091 8 0.003

TABLE 26 Table 26. Age- and sex-adjusted association of 31 SNPs withcancer-related DVT in MEGA (p <= 0.05) Gene Ref- NonRef- Risk ControlCase Case- Control- Marker Symbol RS number Allele Allele Allele RAFModel Parameter P-value OddsRatio OR95l OR95u Genot Count3 Freq3 Count3hCV11466393 TACR1 rs881 C G C 0.830716 additive hCV11466393.GG.GC.adtv0.0301 0.80141 0.6561 0.97891 CC 346 0.7425 3125 hCV11503414 FGGrs2066865 G A A 0.265941 general hCV11503414.AA 0.0001 1.96423 1.38692.78179 GG 196 0.4242 2426 dominant hCV11503414.GG.dom 3E−06 1.613561.3218 1.96967 GG 196 0.4242 2426 recessive hCV11503414.AA.rec 0.00561.59724 1.147 2.22421 GG 196 0.4242 2426 general hCV11503414.AG 4E−051.55126 1.259 1.91134 GG 196 0.4242 2426 additive hCV11503414.AA.AG.adtv1E−06 1.4539 1.2513 1.68933 GG 196 0.4242 2426 hCV11503469 FGG rs2066854T A A 0.266985 general hCV11503469.AA 0.0004 1.87504 1.3257 2.65193 TT199 0.428 2423 dominant hCV11503469.TT.dom 5E−06 1.58923 1.303 1.9383 TT199 0.428 2423 general hCV11503469.AT 5E−05 1.53661 1.2481 1.89177 TT199 0.428 2423 recessive hCV11503469.AA.rec 0.0112 1.53311 1.10212.13262 TT 199 0428 2423 additive hCV11503469.AA.AT.adtv 3E−06 1.427411.2297 1.65692 TT 199 0.428 2423 hCV11503470 rs1800788 C T T 0.208112general hCV11503470.TT 0.0413 1.52638 1.0168 2.29142 CC 271 0.5815 2864dominant hCV11503470.CC.dom 0.0227 1.26127 1.0329 1.54013 CC 271 0.58152864 additive hCV11503470.TT.TC.adtv 0.0118 1.22802 1.0466 1.44086 CC271 0.5815 2864 hCV11786258 KLKB1 rs4253303 G A A 0.393142 generalhCV11786258.AA 0.0038 1.51355 1.1429 2.00443 GG 147 0.3148 1662recessive hCV11786258.AA.rec 0.0109 1.37826 1.0768 1.76415 GG 147 0.31481662 dominant hCV11786258.GG.dom 0.0322 1.25844 1.0198 1.55299 GG 1470.3148 1662 additive hCV11786258.AA.AG.adtv 0.0046 1.22332 1.064 1.40651GG 147 0.3148 1662 hCV11975250 F5 rs6025 C T T 0.026408 generalhCV11975250.TC 1E−06 2.37719 1.6784 3.36683 CC 428 0.8992 4311 dominanthCV11975250.CC.dom 1E−06 2.35148 1.6662 3.31854 CC 428 0.8992 4311additive hCV11975250.TT.TC.adtv 2E−06 2.20614 1.5871 3.06664 CC 4280.8992 4311 hCV15860433 rs2070006 C T T 0.395787 general hCV15860433.TT0.0099 1.47193 1.0975 1.97415 CC 135 0.2922 1665 dominanthCV15860433.CC.dom 0.0013 1.42291 1.1477 1.76413 CC 135 0.2922 1665general hCV15860433.TC 0.0031 1.4064 1.1218 1.76314 CC 135 0.2922 1665additive hCV15860433.TT.TC.adtv 0.0031 1.2365 1.0744 1.42304 CC 1350.2922 1665 hCV15968043 CYP4V2 rs2292423 T A A 0.409182 generalhCV15968043.AA 0.0076 1.458 1.1056 1.92265 TT 143 0.3102 1562 recessivehCV15968043.AA.rec 0.0042 1.42227 1.1178 1.80962 TT 143 0.3102 1562additive hCV15968043.AA.AT.adtv 0.015 1.1906 1.0345 1.37025 TT 1430.3102 1562 hCV1841975 PROC rs1799810 A T T 0.431275 generalhCV1841975.TA 0.0452 1.26045 1.005 1.58086 AA 134 0.2888 1472 hCV1859855GOLGA3/POLE rs2291260 T C C 0.218551 general hCV1859855.CC 5E−05 2.201731.5067 3.21731 TT 263 0.5445 2757 recessive hCV1859855.CC.rec 0.00012.07661 1.434 3.00721 TT 263 0.5445 2757 additive hCV1859855.CC.CT.adtv0.0005 1.3222 1.1293 1.54809 TT 263 0.5445 2757 dominanthCV1859855.TT.dom 0.0148 1.27396 1.0486 1.54776 TT 263 0.5445 2757hCV1874482 ZDHHC6 rs2306158 G A G 0.638875 general hCV1874482.AA 0.0030.57869 0.403 0.83098 GG 205 0.4586 1613 recessive hCV1874482.AA.rec0.0049 0.6086 0.4307 0.86006 GG 205 0.4586 1613 additivehCV1874482.AA.AG.adtv 0.0068 0.81053 0.6962 0.94361 GG 205 0.4586 1613hCV2144411 NDUFB8/SEC31B rs3763695 A G A 0.773979 dominanthCV2144411.AA.dom 0.0498 0.81788 0.669 0.99986 AA 310 0.6418 2736hCV2211618 DDT rs12483950 C G G 0.429318 general hCV2211618.GG 0.04311.32796 1.0088 1.74808 CC 144 0.3013 1478 recessive hCV2211618.GG.rec0.0494 1.26949 1.0006 1.61058 CC 144 0.3013 1478 hCV2303891 APOHrs1801690 C G G 0.054656 general hCV2303891.GG 0.0001 11.0922 3.253737.8146 CC 402 0.8701 4023 recessive hCV2303891.GG.rec 0.0001 10.98453.2237 37.4293 CC 402 0.8701 4023 hCV25990131 CYP4V2 rs13146272 A C A0.64085 dominant hCV25990131.AA.dom 0.0243 0.79512 0.6513 0.97074 AA 2130.4702 1814 additive hCV25990131.CC.CA.adtv 0.0198 0.83799 0.72220.97232 AA 213 0.4702 1814 hCV26175114 TUBA4A rs3731892 A G G 0.108496general hCV26175114.GG 0.0039 2.45516 1.3332 4.52126 AA 371 0.7762 3655recessive hCV26175114.GG.rec 0.0049 2.39667 1.3042 4.40436 AA 371 0.77623655 additive hCV26175114.GG.GA.adtv 0.0226 1.26882 1.034 1.55701 AA 3710.7762 3655 hCV27474895 F11 rs3756011 C A A 0.405226 generalhCV27474895.AA 0.0382 1.35187 1.0165 1.79786 CC 141 0.3045 1619 dominanthCV27474895.CC.dom 0.0202 1.28699 1.0402 1.59237 CC 141 0.3045 1619general hCV27474895.AC 0.0425 1.26294 1.0079 1.5825 CC 141 0.3045 1619additive hCV27474895.AA.AC.adtv 0.0234 1.1738 1.0219 1.34829 CC 1410.3045 1619 hCV27477533 F11 rs3756008 A T T 0.395815 generalhCV27477533.TT 0.0337 1.35365 1.0236 1.79005 AA 152 0.3269 1671 additivehCV27477533.TT.TA.adtv 0.0358 1.15943 1.0099 1.33116 AA 152 0.3269 1671hCV27502514 KLF3 rs3796533 G A A 0.164108 general hCV27502514.AA 0.04671.71209 1.0078 2.90852 GG 308 0.6681 3134 additivehCV27502514.AA.AG.adtv 0.0227 1.23385 1.0298 1.47838 GG 308 0.6681 3134hCV2892877 FGA rs6050 T C C 0.23658 dominant hCV2892877.TT.dom 0.00031.47541 1.1978 1.81744 TT 183 0.441 2237 additive hCV2892877.CC.CT.adtv0.0002 1.46842 1.1983 1.79943 TT 183 0.441 2237 general hCV2892877.CT0.0003 1.46956 1.1923 1.8113 TT 183 0.441 2237 hCV30040828 TNFSF4rs6700269 C T T 0.099423 general hCV30040828.TC 0.0374 1.39291 1.01941.90319 CC 213 0.7662 2257 dominant hCV30040828.CC.dom 0.0342 1.389411.0247 1.88389 CC 213 0.7662 2257 additive hCV30040828.TT.TC.adtv 0.04211.32817 1.0101 1.74635 CC 213 0.7662 2257 hCV3230038 F11 rs2289252 C T T0.403825 general hCV3230038.TT 0.0241 1.38491 1.0436 1.83792 CC 1430.3082 1626 dominant hCV3230038.CC.dom 0.0236 1.27762 1.0334 1.57953 CC143 0.3082 1626 additive hCV3230038.TT.TC.adtv 0.017 1.18364 1.03071.35933 CC 143 0.3082 1626 hCV3230096 CYP4V2 rs3817184 C T T 0.415431general hCV3230096.TT 0.0064 1.46092 1.1125 1.91853 CC 144 0.3103 1546recessive hCV3230096.TT.rec 0.0039 1.41651 1.1182 1.7944 CC 144 0.31031546 additive hCV3230096.TT.TC.adtv 0.0117 1.19499 1.0405 1.37242 CC 1440.3103 1546 hCV3230113 CYP4V2 rs1053094 A T T 0.490487 recessivehCV3230113.TT.rec 0.0189 1.30142 1.0444 1.62169 AA 111 0.2403 1158hCV596331 F9 rs6048 A G A 0.698278 general hCV596331.GG 0.0476 0.764640.5863 0.99719 AA 313 0.644 2719 dominant hCV596331.AA.dom 0.0411 0.80850.6593 0.99142 AA 313 0.644 2719 additive hCV596331.GG.GA.adtv 0.03340.87259 0.7696 0.98931 AA 313 0.644 2719 hCV7422466 C9orf103 rs1052690 AC C 0.196354 recessive hCV7422466.CC.rec 0.0402 1.59328 1.021 2.4864 AA311 0.6466 2630 hCV7459627 WBP11P1 rs1985293 A G G 0.30776 recessivehCV7459627.GG.rec 0.0057 1.50827 1.1268 2.01898 AA 225 0.463 2189general hCV7459627.GG 0.0117 1.48469 1.092 2.01856 AA 225 0.463 2189hCV8726802 F2 rs1799963 G A A 0.009998 additive hCV8726802.AA.AG.adtv5E−06 2.86622 1.8273 4.49576 GG 454 0.9419 4509 dominanthCV8726802.GG.dom 8E−06 2.85006 1.8019 4.50807 GG 454 0.9419 4509general hCV8726802.AG 2E−05 2.75908 1.7344 4.38918 GG 454 0.9419 4509hCV8919444 F5 rs4524 T C T 0.737678 general hCV8919444.CT 0.0322 0.793630.6424 0.9805 TT 272 0.5849 2466 dominant hCV8919444.TT.dom 0.03880.8105 0.664 0.98929 TT 272 0.5849 2466 hCV8957432 RAC2 rs6572 G C G0.55628 general hCV8957432.CC 0.032 0.72918 0.5464 0.97313 GG 169 0.34991439 additive hCV8957432.CC.CG.adtv 0.0353 0.86194 0.7506 0.98985 GG 1690.3499 1439 hCV9102827 GPATCH4 rs3795733 T C C 0.258025 generalhCV9102827.CT 0.0224 1.27189 1.0347 1.56351 TT 246 0.5136 2331 dominanthCV9102827.TT.dom 0.0202 1.26146 1.037 1.53456 TT 246 0.5136 2331additive hCV9102827.CC.CT.adtv 0.0424 1.16745 1.0054 1.35567 TT 2460.5136 2331 Gene Ref- NonRef- Risk Control Control- Case Case- Control-Control- Case- Case- Control- Control- Marker Symbol RS number AlleleAllele Allele RAF Model Freq3 Genot2 Count4 Freq4 Count4 Freq4 Genot3Count5 Freq5 Count5 Freq5 hCV11466393 TACR1 rs881 C G C 0.830716additive 0.691 GC 113 0.2425 1263 0.2793 GG 7 0.015 134 0.0296hCV11503414 FGG rs2066865 G A A 0.265941 general 0.539 AG 217 0.46971756 0.3901 AA 49 0.1061 319 0.0709 dominant 0.539 AG 217 0.4697 17560.3901 AA 49 0.1061 319 0.0709 recessive 0.539 AG 217 0.4697 1756 0.3901AA 49 0.1061 319 0.0709 general 0.539 AG 217 0.4697 1756 0.3901 AA 490.1061 319 0.0709 additive 0.539 AG 217 0.4697 1756 0.3901 AA 49 0.1061319 0.0709 hCV11503469 FGG rs2066854 T A A 0.266985 general 0.538 AT 2170.4667 1757 0.3901 AA 49 0.1054 324 0.0719 dominant 0.538 AT 217 0.46671757 0.3901 AA 49 0.1054 324 0.0719 general 0.538 AT 217 0.4667 17570.3901 AA 49 0.1054 324 0.0719 recessive 0.538 AT 217 0.4667 1757 0.3901AA 49 0.1054 324 0.0719 additive 0.538 AT 217 0.4667 1757 0.3901 AA 490.1054 324 0.0719 hCV11503470 rs1800788 C T T 0.208112 general 0.633 TC163 0.3498 1437 0.3176 TT 32 0.0687 223 0.0493 dominant 0.633 TC 1630.3498 1437 0.3176 TT 32 0.0687 223 0.0493 additive 0.633 TC 163 0.34981437 0.3176 TT 32 0.0687 223 0.0493 hCV11786258 KLKB1 rs4253303 G A A0.393142 general 0.368 AG 224 0.4797 2162 0.4783 AA 96 0.2056 696 0.154recessive 0.368 AG 224 0.4797 2162 0.4783 AA 96 0.2056 696 0.154dominant 0.368 AG 224 0.4797 2162 0.4783 AA 96 0.2056 696 0.154 additive0.368 AG 224 0.4797 2162 0.4783 AA 96 0.2056 696 0.154 hCV11975250 F5rs6025 C T T 0.026408 general 0.949 TC 47 0.0987 226 0.0497 TT 1 0.00217 0.0015 dominant 0.949 TC 47 0.0987 226 0.0497 TT 1 0.0021 7 0.0015additive 0.949 TC 47 0.0987 226 0.0497 TT 1 0.0021 7 0.0015 hCV15860433rs2070006 C T T 0.395787 general 0.369 TC 242 0.5238 2120 0.4701 TT 850.184 725 0.1608 dominant 0.369 TC 242 0.5238 2120 0.4701 TT 85 0.184725 0.1608 general 0.369 TC 242 0.5238 2120 0.4701 TT 85 0.184 7250.1608 additive 0.369 TC 242 0.5238 2120 0.4701 TT 85 0.184 725 0.1608hCV15968043 CYP4V2 rs2292423 T A A 0.409182 general 0.348 AT 215 0.46642178 0.4854 AA 103 0.2234 747 0.1665 recessive 0.348 AT 215 0.4664 21780.4854 AA 103 0.2234 747 0.1665 additive 0.348 AT 215 0.4664 2178 0.4854AA 103 0.2234 747 0.1665 hCV1841975 PROC rs1799810 A T T 0.431275general 0.326 TA 249 0.5366 2195 0.4858 TT 81 0.1746 851 0.1884hCV1859855 GOLGA3/POLE rs2291260 T C C 0.218551 general 0.605 CT 1790.3706 1605 0.3524 CC 41 0.0849 193 0.0424 recessive 0.605 CT 179 0.37061605 0.3524 CC 41 0.0849 193 0.0424 additive 0.605 CT 179 0.3706 16050.3524 CC 41 0.0849 193 0.0424 dominant 0.605 CT 179 0.3706 1605 0.3524CC 41 0.0849 193 0.0424 hCV1874482 ZDHHC6 rs2306158 G A G 0.638875general 0.416 AG 202 0.4519 1724 0.445 AA 40 0.0895 537 0.1386 recessive0.416 AG 202 0.4519 1724 0.445 AA 40 0.0895 537 0.1386 additive 0.416 AG202 0.4519 1724 0.445 AA 40 0.0895 537 0.1386 hCV2144411 NDUFB8/SEC31Brs3763695 A G A 0.773979 dominant 0.598 GA 152 0.3147 1613 0.3524 GG 210.0435 228 0.0498 hCV2211618 DDT rs12483950 C G G 0.429318 general 0.329GC 230 0.4812 2179 0.4843 GG 104 0.2176 842 0.1872 recessive 0.329 GC230 0.4812 2179 0.4843 GG 104 0.2176 842 0.1872 hCV2303891 APOHrs1801690 C G G 0.054656 general 0.892 GC 54 0.1169 481 0.1067 GG 60.013 6 0.0013 recessive 0.892 GC 54 0.1169 481 0.1067 GG 6 0.013 60.0013 hCV25990131 CYP4V2 rs13146272 A C A 0.64085 dominant 0.414 CA 1900.4194 1982 0.4528 CC 50 0.1104 581 0.1327 additive 0.414 CA 190 0.41941982 0.4528 CC 50 0.1104 581 0.1327 hCV26175114 TUBA4A rs3731892 A G G0.108496 general 0.8 GA 93 0.1946 833 0.1824 GG 14 0.0293 79 0.0173recessive 0.8 GA 93 0.1946 833 0.1824 GG 14 0.0293 79 0.0173 additive0.8 GA 93 0.1946 833 0.1824 GG 14 0.0293 79 0.0173 hCV27474895 F11rs3756011 C A A 0.405226 general 0.359 AC 230 0.4968 2134 0.4725 AA 920.1987 763 0.169 dominant 0.359 AC 230 0.4968 2134 0.4725 AA 92 0.1987763 0.169 general 0.359 AC 230 0.4968 2134 0.4725 AA 92 0.1987 763 0.169additive 0.359 AC 230 0.4968 2134 0.4725 AA 92 0.1987 763 0.169hCV27477533 F11 rs3756008 A T T 0.395815 general 0.37 TA 218 0.4688 21150.4683 TT 95 0.2043 730 0.1616 additive 0.37 TA 218 0.4688 2115 0.4683TT 95 0.2043 730 0.1616 hCV27502514 KLF3 rs3796533 G A A 0.164108general 0.697 AG 135 0.2928 1245 0.277 AA 18 0.039 115 0.0256 additive0.697 AG 135 0.2928 1245 0.277 AA 18 0.039 115 0.0256 hCV2892877 FGArs6050 T C C 0.23658 dominant 0.531 CT 229 0.5518 1954 0.4641 CC 30.0072 19 0.0045 additive 0.531 CT 229 0.5518 1954 0.4641 CC 3 0.0072 190.0045 general 0.531 CT 229 0.5518 1954 0.4641 CC 3 0.0072 19 0.0045hCV30040828 TNFSF4 rs6700269 C T T 0.099423 general 0.815 TC 61 0.2194477 0.1721 TT 4 0.0144 37 0.0134 dominant 0.815 TC 61 0.2194 477 0.1721TT 4 0.0144 37 0.0134 additive 0.815 TC 61 0.2194 477 0.1721 TT 4 0.014437 0.0134 hCV3230038 F11 rs2289252 C T T 0.403825 general 0.359 TC 2270.4892 2141 0.4734 TT 94 0.2026 756 0.1671 dominant 0.359 TC 227 0.48922141 0.4734 TT 94 0.2026 756 0.1671 additive 0.359 TC 227 0.4892 21410.4734 TT 94 0.2026 756 0.1671 hCV3230096 CYP4V2 rs3817184 C T T0.415431 general 0.342 TC 212 0.4569 2189 0.4846 TT 108 0.2328 7820.1731 recessive 0.342 TC 212 0.4569 2189 0.4846 TT 108 0.2328 7820.1731 additive 0.342 TC 212 0.4569 2189 0.4846 TT 108 0.2328 782 0.1731hCV3230113 CYP4V2 rs1053094 A T T 0.490487 recessive 0.256 TA 218 0.47192290 0.5066 TT 133 0.2879 1072 0.2372 hCV596331 F9 rs6048 A G A 0.698278general 0.593 GA 92 0.1893 968 0.211 GG 81 0.1667 900 0.1962 dominant0.593 GA 92 0.1893 968 0.211 GG 81 0.1667 900 0.1962 additive 0.593 GA92 0.1893 968 0.211 GG 81 0.1667 900 0.1962 hCV7422466 C9orf103rs1052690 A C C 0.196354 recessive 0.644 CA 144 0.2994 1309 0.3203 CC 260.0541 148 0.0362 hCV7459627 WBP11P1 rs1985293 A G G 0.30776 recessive0.478 GA 197 0.4053 1956 0.4275 GG 64 0.1317 430 0.094 general 0.478 GA197 0.4053 1956 0.4275 GG 64 0.1317 430 0.094 hCV8726802 F2 rs1799963 GA A 0.009998 additive 0.98 AG 27 0.056 92 0.02 AA 1 0.0021 0 0 dominant0.98 AG 27 0.056 92 0.02 AA 1 0.0021 0 0 general 0.98 AG 27 0.056 920.02 AA 1 0.0021 0 0 hCV8919444 F5 rs4524 T C T 0.737678 general 0.548CT 158 0.3398 1713 0.3803 CC 35 0.0753 325 0.0722 dominant 0.548 CT 1580.3398 1713 0.3803 CC 35 0.0753 325 0.0722 hCV8957432 RAC2 rs6572 G C G0.55628 general 0.313 CG 236 0.4886 2242 0.4872 CC 78 0.1615 921 0.2001additive 0.313 CG 236 0.4886 2242 0.4872 CC 78 0.1615 921 0.2001hCV9102827 GPATCH4 rs3795733 T C C 0.258025 general 0.567 CT 193 0.40291440 0.3502 CC 40 0.0835 341 0.0829 dominant 0.567 CT 193 0.4029 14400.3502 CC 40 0.0835 341 0.0829 additive 0.567 CT 193 0.4029 1440 0.3502CC 40 0.0835 341 0.0829

TABLE 27 Table 27. Additive association for 123 finemapping SNPs withDVT in LETS, with LD data from Hapmap (p-value cutoff <= 0.1 in LETS)Additive Model Distance Compari- R- D- Between marker annotation P ValueOR (95% CI) son Finemapping target Squared Prime Targets hDV70683187(rs16846561) 0.022041 1.43 (1.05-1.93) G_vs_C SERPINC1 (hCV16180170) 1 117106 hCV16135173 (rs2146372) 0.033754 1.39 (1.03-1.89) C_vs_G SERPINC1(hCV16180170) 1 1 16648 hCV15956077 SERPINC1 (rs2227611) 0.093487 6.14(0.74-51.16) G_vs_A SERPINC1 (hCV16180170) not not not hapmap hapmaphapmap hCV8911768 SERPINC1 (rs941988) 0.017019 1.46 (1.07-1.98) T_vs_CSERPINC1 (hCV16180170) 1 1 4324 hCV15956034 SERPINC1 (rs2227603)0.077266 1.71 (0.94-3.09) A_vs_C SERPINC1 (hCV16180170) 0.0129 0.20263669 hCV15956059 SERPINC1 (rs2227592) 0.022768 1.44 (1.05-1.96) T_vs_CSERPINC1 (hCV16180170) 1 1 505 hCV16180170 SERPINC1 (rs2227589) 0.0257491.42 (1.04-1.94) T_vs_C SERPINC1 (hCV16180170) 1 1 1 hCV11975658(rs1951626) 0.078232  1.2 (0.98-1.47) A_vs_G SERPINC1 (hCV16180170)0.204 1 5886 hDV70683212 RC3H1 (rs16846593) 0.044415 1.45 (1.01-2.07)G_vs_C SERPINC1 (hCV16180170) 0.425 1 12002 hCV30440155 (rs6699146)0.061774 1.19 (0.99-1.43) C_vs_G SERPINC1 (hCV16180170) 0.1123 1 173307hCV30205817 RABGAP1L (rs10489254) 0.073088 1.42 (0.97-2.09) T_vs_CSERPINC1 (hCV16180170) 0.3247 0.7784 311586 hCV25932979 RABGAP1L(rs16846809) 0.096111 1.38 (0.94-2.02) G_vs_A SERPINC1 (hCV16180170)0.2519 0.7228 333183 hDV70683382 RABGAP1L (rs16846815) 0.040023 1.49(1.02-2.18) C_vs_G SERPINC1 (hCV16180170) 0.3247 0.7784 334327 hCV815038RGS7 (rs390488) 0.096645 1.18 (0.97-1.43) T_vs_C RGS7 (hCV916107) 0.12980.6645 92924 hCV1703855 RGS7 (rs261828) 0.082919 1.19 (0.98-1.44) C_vs_TRGS7 (hCV916107) 0.1108 0.6027 90577 hCV1703867 RGS7 (rs261861) 0.0283051.24 (1.02-1.5) T_vs_C RGS7 (hCV916107) 0.0283 0.2557 66200 hCV29269378RGS7 (rs6657406) 0.085115 1.49 (0.95-2.36) G_vs_A RGS7 (hCV916107)0.0129 1 56263 hCV30626715 RGS7 (rs6690744) 0.058389  1.2 (0.99-1.45)G_vs_T RGS7 (hCV916107) 0.2435 0.7882 28216 hCV31714450 RGS7 (rs6429232)0.039477 1.22 (1.01-1.48) T_vs_C RGS7 (hCV916107) 0.2201 0.7854 27206hCV26887403 RGS7 (rs6682084) 0.054414  1.2 (1-1.44) C_vs_A RGS7(hCV916107) 0.279 0.6754 26666 hCV1703892 RGS7 (rs3893179) 0.086181 1.18(0.98-1.43) T_vs_A RGS7 (hCV916107) 0.2315 0.7973 26412 hCV27878067 RGS7(rs4660016) 0.069991 1.19 (0.99-1.44) G_vs_A RGS7 (hCV916107) 0.23150.7973 26331 hCV27956129 RGS7 (rs4659585) 0.072323 1.19 (0.98-1.44)A_vs_C RGS7 (hCV916107) 0.2315 0.7973 26266 hCV8857351 RGS7 (rs2341021)0.073263 1.19 (0.98-1.43) T_vs_C RGS7 (hCV916107) 0.2315 0.7973 21760hCV1703910 RGS7 (rs3911618) 0.033677 1.23 (1.02-1.48) A_vs_G RGS7(hCV916107) 0.263 0.8034 16533 hCV26887434 RGS7 (rs12723522) 0.056937 1.2 (0.99-1.45) C_vs_A RGS7 (hCV916107) 0.2787 0.8674 14037 hCV8856223RGS7 (rs1382243) 0.039025 1.22 (1.01-1.47) G_vs_C RGS7 (hCV916107)0.3276 0.7273 7275 hCV916106 RGS7 (rs575226) 0.021282 1.26 (1.04-1.54)A_vs_G RGS7 (hCV916107) 1 1 128 hCV916107 LOC729138 (rs670659) 0.0179441.27 (1.04-1.54) C_vs_T RGS7 (hCV916107) 1 1 1 hCV26887464 RGS7(rs6669640) 0.092625 1.18 (0.97-1.43) A_vs_G RGS7 (hCV916107) 0.61310.874 6356 hCV31056155 SDCCAG8 (rs12131952) 0.018087 1.74 (1.1-2.75)G_vs_C AKT3 (hCV233148) 0.0258 1 81464 hCV15755949 SDCCAG8 (rs2997494)0.098814 1.35 (0.94-1.94) G_vs_A AKT3 (hCV233148) 0.0403 1 54670hCV26338482 SDCCAG8 (rs10803143) 0.050211 1.23 (1-1.51) T_vs_C AKT3(hCV233148) 0.1943 0.4617 53762 hCV26338512 SDCCAG8 (rs2994339) 0.0029761.41 (1.12-1.77) G_vs_A AKT3 (hCV233148) 0.4321 0.8476 27931 hCV26338513AKT3 (rs3006917) 0.004793 1.39 (1.1-1.74) T_vs_C AKT3 (hCV233148) 0.47740.8689 27380 hCV26034157 LOC729199 (rs2994329) 0.012253 1.32 (1.06-1.64)T_vs_C AKT3 (hCV233148) 0.5147 0.8759 21430 hCV30690784 SDCCAG8(rs4658574) 0.01138 1.32 (1.06-1.64) C_vs_T AKT3 (hCV233148) 0.74420.9033 18635 hCV26034142 AKT3 (rs9428576) 0.024681 1.23 (1.03-1.47)C_vs_T AKT3 (hCV233148) 0.4446 1 7324 hCV12073840 AKT3 (rs14403)0.005929 1.36 (1.09-1.69) T_vs_C AKT3 (hCV233148) 0.8697 1 5458hCV9493081 AKT3 (rs1058304) 0.000379 1.45 (1.18-1.78) T_vs_C AKT3(hCV233148) 1 1 4494 hCV233148 AKT3 (rs1417121) 0.000345 1.45(1.18-1.78) C_vs_G AKT3 (hCV233148) 1 1 1 hCV30690777 AKT3 (rs12045585)0.035416 1.32 (1.02-1.72) A_vs_G AKT3 (hCV233148) 0.3153 0.8291 3750hCV30690778 AKT3 (rs12140414) 0.002597 1.44 (1.14-1.82) C_vs_T AKT3(hCV233148) 0.5904 0.9381 5038 hCV97631 AKT3 (rs1538773) 9.68E−05 1.55(1.24-1.92) G_vs_T AKT3 (hCV233148) 0.6656 0.9434 5333 hCV30690780 AKT3(rs10737888) 3.78E−05 1.58 (1.27-1.96) C_vs_A AKT3 (hCV233148) 0.66560.9434 9134 hCV8688111 AKT3 (rs1578275) 0.001215 1.49 (1.17-1.89) C_vs_GAKT3 (hCV233148) 0.5904 0.9381 11093 hCV26719108 AKT3 (rs10927035)0.001896 1.36 (1.12-1.66) C_vs_T AKT3 (hCV233148) 0.2417 0.7058 34633hCV29210363 AKT3 (rs6656918) 5.24E−05 1.56 (1.26-1.94) G_vs_A AKT3(hCV233148) 0.656 0.941 36875 hCV26719113 AKT3 (rs7517340) 0.000163 1.58(1.24-2) T_vs_C AKT3 (hCV233148) 0.3991 0.9147 40841 hCV26719121 AKT3(rs10927041) 0.000111 1.59 (1.26-2) C_vs_T AKT3 (hCV233148) 0.5615 162541 hCV31523608 AKT3 (rs12744297) 0.005758 1.32 (1.08-1.61) G_vs_AAKT3 (hCV233148) 0.1547 0.4381 64947 hCV31523638 AKT3 (rs12037013)0.002893 1.49 (1.15-1.93) A_vs_G AKT3 (hCV233148) 0.382 0.9142 114858hCV31523643 AKT3 (rs6671475) 0.000377 1.52 (1.21-1.91) G_vs_A AKT3(hCV233148) 0.4875 0.9224 119993 hCV31523557 AKT3 (rs10754807) 0.0001791.57 (1.24-1.98) A_vs_G AKT3 (hCV233148) 0.4481 0.9239 134809hCV15885425 AKT3 (rs2290754) 0.000145 1.57 (1.24-1.97) C_vs_A AKT3(hCV233148) 0.4499 0.9244 136919 hCV1678682 AKT3 (rs320339) 0.00034 1.51(1.21-1.9) T_vs_G AKT3 (hCV233148) 0.3838 0.9147 201561 hCV1678674 AKT3(rs1458023) 0.000408  1.5 (1.2-1.88) C_vs_T AKT3 (hCV233148) 0.35170.9089 217324 hCV26719227 AKT3 (rs10927065) 0.009997  1.4 (1.08-1.8)A_vs_C AKT3 (hCV233148) 0.3517 0.9089 245262 hCV26719154 AKT3(rs11588042) 0.025097 1.79 (1.08-2.98) T_vs_C AKT3 (hCV233148) 0.0097 1265282 hCV31523650 AKT3 (rs12048930) 0.000974 1.47 (1.17-1.86) T_vs_CAKT3 (hCV233148) 0.3459 0.7848 270727 hCV31523658 AKT3 (rs12047209)0.006153 1.43 (1.11-1.85) C_vs_A AKT3 (hCV233148) 0.317 0.8314 285058hCV15953063 (rs2953331) 0.041925 1.22 (1.01-1.48) A_vs_G AKT3(hCV233148) 0.0556 0.2841 354919 hCV134275 C3orf15 (rs9847068) 0.0658681.21 (0.99-1.48) G_vs_A NR1I2 (hCV263841) 0.5453 0.8675 76427 hCV134278C3orf15 (rs9848716) 0.085183 1.19 (0.98-1.46) T_vs_C NR1I2 (hCV263841)0.329 0.8118 74733 hCV30699692 C3orf15 (rs6781992) 0.078978 1.66(0.94-2.94) C_vs_T NR1I2 (hCV263841) 0.1035 1 47857 hCV1834242 C3orf15(rs11712308) 0.005499  1.3 (1.08-1.56) G_vs_A NR1I2 (hCV263841) 0.54860.9531 17773 hCV1833991 NR1I2 (rs11926554) 0.057578 1.25 (0.99-1.58)C_vs_T NR1I2 (hCV263841) 0.5548 1 5484 hCV263841 NR1I2 (rs1523127)0.000146 1.44 (1.19-1.73) C_vs_A NR1I2 (hCV263841) 1 1 1 hCV30747430NR1I2 (rs11712211) 0.014443 1.35 (1.06-1.71) T_vs_C NR1I2 (hCV263841)0.176 1 3102 hCV11503470 (rs1800788) 0.013778 1.32 (1.06-1.65) T_vs_CFGG (hCV11503469) 0.3992 0.7151 51268 hCV15860433 (rs2070006) 0.0239131.24 (1.03-1.5) T_vs_C FGG (hCV11503469) 0.5455 1 21316 hCV2892869(rs13109457) 0.002493 1.37 (1.12-1.68) A_vs_G FGG (hCV11503469) 0.91490.9565 20303 hCV27020269 (rs7659613) 0.027027 1.24 (1.02-1.49) C_vs_GFGG (hCV11503469) 0.5455 1 19766 hCV31863982 (rs7659024) 0.000205 1.48(1.2-1.82) A_vs_G FGG (hCV11503469) 0.9579 1 14252 hCV7429782 FGG(rs1118823) 0.014285  1.3 (1.05-1.6) T_vs_A FGG (hCV11503469) 0.1442 111336 hCV11503414 FGG (rs2066865) 0.000446 1.45 (1.18-1.78) A_vs_G FGG(hCV11503469) 0.9579 1 9906 hCV11503431 FGG (rs2066861) 0.000351 1.46(1.19-1.8) T_vs_C FGG (hCV11503469) 0.9579 1 7746 hCV11503469 FGG(rs2066854) 0.000205 1.48 (1.2-1.83) A_vs_T FGG (hCV11503469) 1 1 1hCV11853483 FGG (rs12644950) 0.000278 1.47 (1.19-1.81) A_vs_G FGG(hCV11503469) 0.9545 1 2141 hCV2892855 FGG (rs6536024) 0.0009 1.39(1.14-1.68) C_vs_T FGG (hCV11503469) 0.2597 1 8189 hCV11853496 FGG(rs7654093) 0.000364 1.46 (1.18-1.79) T_vs_A FGG (hCV11503469) 0.9576 19892 hCV25990131 CYP4V2 (rs13146272) 0.04894 1.22 (1-1.49) A_vs_C CYP4V2(hCV25990131) 1 1 1 hCV3230099 CYP4V2 (rs3736456) 0.075392 1.49(0.96-2.32) T_vs_C CYP4V2 (hCV25990131) 0.119 1 2145 hCV3230016 KLKB1(rs4253325) 0.044164 1.37 (1.01-1.86) G_vs_A CYP4V2 (hCV25990131) 0.00970.2187 58263 hCV25634754 KLKB1 (rs4253331) 0.005773  1.7 (1.17-2.48)C_vs_T CYP4V2 (hCV25990131) 0.0545 1 58925 hCV27477533 (rs3756008)0.030992 1.22 (1.02-1.46) T_vs_A CYP4V2 (hCV25990131) 0.1626 0.631265175 hCV8241630 F11 (rs925451) 0.045183  1.2 (1-1.44) A_vs_G CYP4V2(hCV25990131) 0.1371 0.6445 67359 hCV25474414 F11 (rs4253399) 0.0231781.23 (1.03-1.48) G_vs_T CYP4V2 (hCV25990131) 0.1211 0.5547 67884hCV25474413 F11 (rs3822057) 0.066697 1.19 (0.99-1.42) C_vs_A CYP4V2(hCV25990131) 0.1545 0.4747 67942 hCV12066124 F11 (rs2036914) 0.0132741.27 (1.05-1.53) C_vs_T CYP4V2 (hCV25990131) 0.1525 0.456 72271hCV3230030 F11 (rs4253408) 0.04234 1.43 (1.01-2.01) A_vs_G CYP4V2(hCV25990131) 0.0486 1 73648 hCV27474895 F11 (rs3756011) 0.035267 1.21(1.01-1.45) A_vs_C CYP4V2 (hCV25990131) 0.1303 0.6017 86039 hCV3230038F11 (rs2289252) 0.061325 1.19 (0.99-1.42) T_vs_C CYP4V2 (hCV25990131)0.1185 0.5845 87171 hCV3230136 LOC728284 (rs13116273) 0.092188  1.2(0.97-1.48) G_vs_A CYP4V2 (hCV25990131) 0.0006 0.0282 97676 hCV29821005LOC728284 (rs6552970) 0.088436 1.22 (0.97-1.53) T_vs_C CYP4V2(hCV25990131) 0.0012 0.0582 118016 hCV32209620 LOC728284 (rs6552972)0.088796 1.21 (0.97-1.52) C_vs_T CYP4V2 (hCV25990131) 0.0012 0.0582118194 hCV32209605 LOC728284 (rs6829128) 0.097805 1.17 (0.97-1.42)T_vs_C CYP4V2 (hCV25990131) 0.0101 0.204 136794 hCV1376207 NLRP2(rs11672113) 0.081881 1.18 (0.98-1.43) G_vs_C GP6 (hCV8717873) 0.1120.8676 41715 hCV8717949 NLRP2 (rs1654495) 0.079445 1.18 (0.98-1.43)C_vs_A GP6 (hCV8717873) 0.1439 0.858 35017 hCV1376227 NLRP2 (rs1671133)0.071931 1.19 (0.98-1.43) C_vs_A GP6 (hCV8717873) 0.1501 0.8785 29547hCV8717916 NLRP2 (rs1043673) 0.0279 1.24 (1.02-1.5) A_vs_C GP6(hCV8717873) 0.1296 0.8728 24364 hCV8717893 GP6 (rs1671192) 0.0853611.22 (0.97-1.54) G_vs_A GP6 (hCV8717873) 0.8755 1 6663 hCV1376342 GP6(rs1654416) 0.081328 1.23 (0.97-1.54) T_vs_C GP6 (hCV8717873) 0.838 16561 hCV8717873 GP6 (rs1613662) 0.01299 1.36 (1.07-1.74) A_vs_G GP6(hCV8717873) 1 1 1 hCV8717752 RDH13 (rs1671217) 0.024278 1.34(1.04-1.72) G_vs_A GP6 (hCV8717873) 0.8868 1 17638 hCV29271569 RDH13(rs1626971) 0.014499 1.36 (1.06-1.75) T_vs_C GP6 (hCV8717873) 0.8868 120430 hCV8703249 RDH13 (rs1654444) 0.051859 1.28 (1-1.64) G_vs_T GP6(hCV8717873) 0.8868 1 29860 hCV27904396 (rs4829996) 0.056818 1.19(1-1.41) G_vs_A F9 (hCV596331) 0.2533 0.6172 42147 hCV596663 (rs411017)0.013879 1.23 (1.04-1.45) G_vs_A F9 (hCV596331) 0.2537 0.5796 21179hCV2288095 F9 (rs378815) 0.01722 1.22 (1.04-1.44) C_vs_T F9 (hCV596331)0.2537 0.5796 21084 hCV2986575 F9 (rs4149674) 0.071573 1.16 (0.99-1.37)A_vs_T F9 (hCV596331) 0.6414 0.8782 16480 hCV596669 F9 (rs376165)0.06633 1.16 (0.99-1.37) A_vs_G F9 (hCV596331) 0.7113 0.9583 15548hCV596326 F9 (rs398101) 0.017442 1.23 (1.04-1.45) A_vs_G F9 (hCV596331)0.8216 0.9064 9324 hCV596330 F9 (rs422187) 0.047525 1.19 (1-1.41) A_vs_CF9 (hCV596331) 1 1 422 hCV596331 F9 (rs6048) 0.026883 1.21 (1.02-1.44)A_vs_G F9 (hCV596331) 1 1 1 hDV76976792 F9 (rs4149759) 0.05842 1.31(0.99-1.74) T_vs_C F9 (hCV596331) 0.0744 0.596 1775 hCV596335 F9(rs413957) 0.080856 1.19 (0.98-1.44) C_vs_G F9 (hCV596331) 0.4049 0.93194237 hCV596336 F9 (rs110583) 0.07609 1.19 (0.98-1.44) T_vs_C F9(hCV596331) 0.4049 0.9319 5252 hCV596337 F9 (rs421766) 0.059328 1.21(0.99-1.46) G_vs_C F9 (hCV596331) 0.4049 0.9319 94835 hDV76976795 F9(rs4149762) 0.072018 1.34 (0.97-1.85) A_vs_G F9 (hCV596331) 0.00650.1534 8918 hCV2969899 (rs434144) 0.030535 1.23 (1.02-1.49) C_vs_G F9(hCV596331) 0.343 0.8128 13146 hDV70941043 (rs17342358) 0.056568 4.08(0.96-17.3) G_vs_A F9 (hCV596331) 0.0123 1 21299 hCV15952952 MCF2(rs2235708) 0.057867 4.05 (0.95-17.15) G_vs_A F9 (hCV596331) 0.0123 145465

1. A method of determining whether a human has an altered risk forvenous thrombosis (VT), comprising testing nucleic acid from said humanfor the presence or absence of a polymorphism selected from the groupconsisting of the polymorphisms represented by position 101 of any oneof the nucleotide sequences of SEQ ID NOS:602-1587 or its complement,wherein the polymorphism indicates an altered risk for VT.
 2. The methodof claim 1, wherein the VT is deep vein thrombosis (DVT).
 3. The methodof claim 1, wherein said polymorphism is selected from the groupconsisting of the polymorphisms provided in at least one of Tables 5-9and 11-30.
 4. The method of claim 1, wherein the altered risk is anincreased risk.
 5. The method of claim 1, wherein the altered risk is adecreased risk.
 6. The method of claim 1, wherein said nucleic acid is anucleic acid extract from a biological sample from said human.
 7. Themethod of claim 6, wherein said biological sample is blood, saliva, orbuccal cells.
 8. The method of claim 6, further comprising preparingsaid nucleic acid extract from said biological sample prior to saidtesting step.
 9. The method of claim 8, further comprising obtainingsaid biological sample from said human prior to said preparing step. 10.The method of claim 1, wherein said testing step comprises nucleic acidamplification.
 11. The method of claim 10, wherein said nucleic acidamplification is carried out by polymerase chain reaction.
 12. Themethod of claim 1, further comprising correlating the presence orabsence of the polymorphism with an altered risk for VT.
 13. The methodof claim 12, wherein said correlating step is performed by computersoftware.
 14. The method of claim 1, wherein said testing is performedusing sequencing, 5′ nuclease digestion, molecular beacon assay,oligonucleotide ligation assay, size analysis, single-strandedconformation polymorphism analysis, or denaturing gradient gelelectrophoresis (DGGE).
 15. The method of any one of claim 1, whereinsaid testing is performed using an allele-specific method.
 16. Themethod of claim 15, wherein said allele-specific method isallele-specific probe hybridization, allele-specific primer extension,or allele-specific amplification.
 17. The method of claim 16, whereinthe method is performed using an allele-specific primer provided inTable
 3. 18. The method of claim 1 which is an automated method.
 19. Themethod of claim 1, wherein the VT is recurrent VT.
 20. The method ofclaim 19, wherein the polymorphism is selected from the group consistingof the polymorphisms provided in Table
 24. 21. The method of claim 1,wherein the VT includes pulmonary embolism (PE).
 22. The method of claim21, wherein the polymorphism is selected from the group consisting ofthe polymorphisms provided in Table
 25. 23. The method of claim 1,wherein the human has cancer.
 24. The method of claim 23, wherein thepolymorphism is selected from the group consisting of the polymorphismsprovided in Table
 26. 25. A method for reducing risk of venousthrombosis (VT) in a human, comprising administering to said human aneffective amount of a therapeutic agent, said human having beenidentified as having an increased risk for VT due to the presence orabsence of a polymorphism selected from the group consisting of thepolymorphisms represented by position 101 of any one of the nucleotidesequences of SEQ ID NOS:602-1587 or its complement.
 26. The method ofclaim 25, wherein the method comprises testing nucleic acid from saidhuman for the presence or absence of said polymorphism.
 27. The methodof claim 25, wherein the therapeutic agent comprises an anticoagulantagent.
 28. The method of claim 27, wherein the anticoagulant agent isselected from the group consisting of coumarines (vitamin K antagonists)such as warfarin (coumadin), acenocoumarol, phenprocoumon, andphenindione; heparin and derivative substances such as low molecularweight heparin; factor Xa inhibitors such as Fondaparinux, Idraparinux,and other synthetic pentasaccharide inhibitors of factor Xa; andthrombin inhibitors such as argatroban, lepirudin, bivalirudin, anddabigatran.
 29. The method of claim 25, wherein the therapeutic agentcomprises an antiplatelet agent.
 30. The method of claim 29, wherein theantiplatelet agent is selected from the group consisting ofcyclooxygenase inhibitors such as aspirin, and ADP receptor inhibitorssuch as clopidogrel (Plavix) and prasugrel (Effient).
 31. A method ofidentifying a human having an increased risk for venous thrombosis (VT),comprising testing a nucleic acid sample from said human for thepresence or absence of a first polymorphism which is in linkagedisequilibrium with a second polymorphism, wherein the secondpolymorphism is a polymorphism selected from the group consisting of thepolymorphisms represented by position 101 of any one of the nucleotidesequences of SEQ ID NOS:602-1587 or its complement, and wherein thefirst polymorphism identifies said human as having an increased risk forVT.
 32. The method of claim 31, wherein the linkage disequilibrium isr²=1.
 33. The method of claim 31, wherein the first polymorphism isselected from the group consisting of the polymorphisms set forth inTable
 4. 34. The method of claim 31, further comprising correlating thepresence or absence of said first polymorphism with an increased riskfor VT.
 35. The method of claim 34, wherein said correlating step isperformed by computer software.
 36. The method of claim 1, furthercomprising at least one of: a) selecting said human for inclusion in aclinical trial of a therapeutic agent; and b) assigning said human to agroup within a clinical trial.
 37. The method of claim 36, wherein thetherapeutic agent is an anticoagulant agent or an antiplatelet agent.38. A kit for determining whether a human has an altered risk for venousthrombosis (VT), wherein the kit comprises at least one container and atleast one polynucleotide detection reagent stored in said container,wherein the polynucleotide detection reagent is capable of detecting thepresence or absence of a polymorphism selected from the group consistingof the polymorphisms represented by position 101 of any one of thenucleotide sequences of SEQ ID NOS:602-1587 or its complement.
 39. Thekit of claim 38, wherein the polynucleotide detection reagentselectively hybridizes to said nucleic acid in the presence of saidpolymorphism and does not hybridize to said nucleic acid in the absenceof said polymorphism.